Method for predicting biological activity of antibiotics, and novel non beta-lactam antibacterial agents derived therefrom
This invention relates to novel antibacterial agents and a method for predicting the activity thereof relative to penicillin. More particularly, this application describes a molecular modelling technique for determining the fit and reactivity of candidate compounds with bacterial cell wall receptors, and hence a method for predicting structural types that exhibit activity.
It has been known since the 1940's that β-lactam
antibiotics, such as the penicillins and cephalosporins, are effective by reason of their interference with the integrity of bacterial cell walls. It has also been discovered that the interference is effected by covalent bonding to the active site serine residue of one or more of a group of enzymes termed penicillin binding proteins (PBP's). These enzymes serve to complete bacterial cell wall synthesis by a cross linking of peptidoglycan chains, and are essential to the cells. All known PBP's include a sequence -Ser-X-X-Lys- and the simplest kinetic description of the reaction between a PBP and a β-lactam antibiotic is given in equation 1, below, where A is a generalized structure. Since the PBP is regenerated in the deacylation step, useful antibacterial activity is considered to require k
3/K ≥ 1000 M
-1 sec
-1 and k
4 ≤ 1 x 10
-4 sec
-1.
3 U (
The question is, therefore, what is the correlation, if any, between antibacterial activity and the "lock-and-key" interactions which take place between the PBP and the antibiotic.
It is an object of the present invention to determine the correlation between antibacterial activity and the lock-and-key interactions between PBP's and selected antibiotics and thus provide a means by which the "fit" (Step 1) and
"reactivity" (Step 2) of any selected candidate structure relative to the fit and reactivity of penicillin may be predicted with some degree of quantitative accuracy.
It is another object of this invention to design with this model novel non β-lactam compounds having antibacterial activity.
One aspect of the present invention provides a method of determining the molecular structure of large molecules wherein the strain energy of the molecule is minimized in terms of molecular parameters, characterized in that in order to identify starting parameters for the minimization procedure the one-point energies of a large number of most
probable random structures are first calculated, and a predetermined number of said random structures having the lowest energies are selected for said minimization
procedure. Thus by another aspect of this invention there is provided a method for determining fit and reactivity of any selected candidate antibacterial compound comprising (a) simulating the reaction of said compound with a model of a penicillin binding protein which includes a serine-lysine active site, by determining the relative ease of formation of a four-centred relationship between OH of said serine and a
reactive site of said compound; and (b) determining the activation energy for the four-centred reaction of the chemically active functional group of said compound with methanol relative to the activation energy of the
corresponding reaction of methanol with N-methylazetidinone.
Another aspect of this invention provides a non-β-lactam containing compound characterized in that said compound is capable of forming a four-centred transition structure which includes a serine OH group contained in a model of a
penicillin binding protein, reacted therewith; said compound having an activation energy for reaction with methanol not greater than 3 kcal/mol higher than the activation energy exhibited by N-methyl- azetidinone. Another aspect of this invention provides compounds of the formula:
Z R
where
X is selected from S, O, CH2, NH, NR7, and Se
Y is selected from OH, NH2, NHCOR9, and SH
R1, R2, R3, R4, R5, R6, R7, are each hydrogen, alkyl, or aryl, and
R9 is a β-lactam active side chain,
and pharmaceutically acceptable salts thereof.
β-lactam active side chains are side chains known to be active in β-lactam antibiotics. As used herein, the
substituents acceptable in beta-lactam antibiotics may be any of the wide range of permissible substituents disclosed in the literature pertaining to penicillin and cephalosporin compounds. Such substituents may, for example, comprise a group of the formula
-XQ
wherein X represents oxygen or sulfur and Q represents C1-4 alkyl (e.g., methyl or ethyl), C2-4 alkenyl (e.g. vinyl or propenyl) or aryl C1-4 alkyl (e.g., phenyl C1-4 alkyl such as benzyl).
Such substituents also may be, for example, an unsaturated organic group, for example, a group of the formula
wherein R1 and R2 which may be the same or different, and are each selected from hydrogen, carboxy, cyano, C2-7 alkoxycarbonyl (e.g., methoxycarbonyl or ethoxycarbonyl), and substituted or unsubstituted aliphatic (e.g., alkyl, preferably C1-C6 alkyl such as methyl, ethyl, isopropyl or n-propyl). Specific substituted vinyl groups of the above formula include 2-carboxyvinyl, 2-methoxycarbonylvinyl, 2-ethoxycarbonylvinyl and 2-cyanovinyl. Alternatively, the β-lactam acceptable substituent may also be an unsubstituted or substituted methyl group depicted by the formula
-CH2Y wherein Y is a hydrogen atom or a nucleophilic atom or group, e.g., the residue of a nucleophile or a derivative of a residue of a nucleophile. Y may thus, for example, be derived from the wide range of nucleophilic substances characterized by possessing a nucleophilic nitrogen, carbon, sulfur or oxygen atom. Such nucleophiles have been widely
described in the patent and technical literature respecting β-lactam chemistry and are exemplified, for example, in Foxton et al U.S. Patent No. 4,385,177 granted May 24, 1983, at column 4, line 42 - column 8, line 24 and column 34, line 51 - column 36, line 17, the disclosure of which is
incorporated by this reference herein.
Yet another aspect of this invention provides compounds of the formula:
where
X is selected from S, O, CH2, NH, NR8, and Se
Y is selected from OH, NH2, NHCOR9, and SH
R1, R2, R3, R4, R5, R6, R7, R8 are each hydrogen, alkyl, or aryl, and
R9 is a a β-lactam active side chain,
and pharmaceutically acceptable salts thereof
A further aspect of this invention provides compounds of the formula:
where
X-Y is selected from S-S, CH2CH2, S-CH2, CH2-S, S-NR8, NR8-S ,
CH2H-O, O-CH2, O-NR8, NR8-O, Se-Se, CH2-CH2, and Se-CH2
Z is selected from OH, NH2, NHCOR9, and SH
R1, R2, R3, R4, R5, R6, R8 are each hydrogen, alkyl, aryl
R7 is alkyl, or aryl, and
R9 is a β-lactam active side chain,
and pharmaceutically acceptable salts thereof
A still further aspect of the invention provides compounds of the formula:
where
X is selected from S, O, CH2, NH, NR6, and Se
Y is selected from N, CH, and CR7
Z is OH, NH2, SH, or NHCOR9 (when Y=N)
Z is R10 (when Y=CH, or CR7)
R1=R2=R3=R4=R5=R6=R7= are each hydrogen, alkyl, or aryl, and
R9 is a β-lactam active side chain
where R11 is alkyl, or aryl, and
R12=OH, NH2, NHCOR9, SH
and pharmaceutically acceptable salts thereof. Another aspect of the invention provides compounds of the formula:
where
X is selected from S, O, CH2, NH, NR5, and Se
Y is NR6- Z, and
R1, R2, R3, R4, R5, and R6 are each H, alkyl, or aryl
Z is OH, SH, NH2, or NHCOR7
R9 is a β-lactam active side chain,
and pharmaceutically acceptable salts thereof. Preferably,
R6 is hydrogen and Z is NHCOR9 where R9 is lower alkyl and particularly benzyl.
As used herein, the term "alkyl" includes alkyl groups containing up to twenty carbon atoms, preferably C1-6 alkyl groups, which can optionally be monosubstituted, distributed or polysubstituted by functional groups, for example by free, etherified is esterified hydroxyl or mercapto groups, such as lower alkoxy or lower alkylthio; optionally
substituted lower alkoxycarbonyloxy or lower alkanoyloxy; halogen; oxo; nitro; optionally substituted amino, for example lower alkylamino, di-lower alkylamino, lower
alkyleneamino, oxo-lower alkyleneamino or aza-lower
alkyleneamino, as well as acylamino, such as lower
alkanoylamino, lower alkoxycarbonylamino, halogeno-lower alkoxycarbonylamino, optionally substituted phenyl-lower alkoxycarbonylamino, optionally substitutedcarbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, and also sulfoamino which is optionally present in the form of a salt, such as in the form of an alkali metal salt, azido, or acyl, such as lower alkanoyl or benzoyl;
Optionally functionally modified carboxyl, such as carboxyl present in the form of a salt, esterified carboxyl, such as lower alkoxycarbonyl, optionally substituted carbamoyl, such as N-lower alkylcarbamoyl or N, N-di-lower alkylcarbamoyl and also optionally substituted ureidocarbonyl or
guanidinocarbonyl; nitrile; optionally functionally modified sulfo, such as sulfamoyl or sulfo present in the form of a salt; or optionally O-monosubstituted or O, O-disubstituted phosphono, which may be substituted, for example, by
optionally substituted lower alkyl, phenyl or phenyl-lower alkyl, it also being possible for O-unsubstituted or O-monosubstituted phosphono to be in the form of a salt, such as in the form of an alkali metal salt.
As used herein, the term "aryl" includes carbocyclic, hetrocyclic aryl. The carbocyclic aryl includes phenyl and naphthyl, optionally substituted with up to three halogen, C1-6 alkyl, C1-6 alkoxy, halo (C1-6) alkyl, hydroxy, amino, carboxy, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonyl-(C1-6)-alkyl, nitro, sulfonamido, C1-6 alkylcarbonyl, amido (-CONH2), or C1- 6 alkylamino groups.
The term "heterocyclic" includes single or fused rings comprising up to four hetro atoms in the ring selected from
oxygen, nitrogen and sulphur and optionally substituted with up to three three halogen C3-6 alkyl, C1-6 alkoxy, halo (C1-6) alkyl, hydroxy, amino, carboxy, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonyl (C1-6) alkyl, aryl, oxo, nitro, sulphonamido, C1-6 alkyl-carbonyl, amido or C1-6 alkylamino groups.
Suitable C1-6 alkyl groups may be straight or branched chain and include methyl, ethyl n- or iso-propyl, n-, sec-, iso-, or tert-butyl. In those cases where the C1-6 alkyl group carries a substituent the preferred C1-6 alkyl groups include methyl, ethyl and n-propyl.
The invention will now be described in more detail, by way of example only, with reference to the accompanying drawings in which:
Figure 1 shows the structure of a model of a penicillin receptor whose docking to penicillins and
cephalosporins leads uniformly to four-centered
interactions between C-O-H of serine and (o) C-N of the penicillin or cephalosporin;
Figure 2 is a stereoscopic view of penicillin V docked to the peptide of Figure 1;
Figure 3 is a stereoscopic view of a ▲3-cephalosporin docked to the peptide of Figure 1;
Figure 4 is a stereoscopic view of a ▲2-cephalosporin docked to the peptide of Figure 1; Figure 5 is a stereoscopic view of a 4-epi-▲2- cephalosporin docked to the peptide of Figure 1;
Figure 6 is a close-up view of the four-centred
interaction between C-O-H of serine and (O)C-N of the β-lactam ring which exists in Figure 2;
Figure 7 shows the N-protonated transition structure for the attack of methanol upon the exo face of N- methylazetidinone (ab initio calculation);
Figure 8 is the O-protonated transition structure for the attack of methanol upon the exo face of N- methylazetidinone (ab initio calculation). Figure 9 is a stereoscopic view of the transition structure calculated using MINDO/3 for the reaction of methanol with a penicillin via an N-protonated pathway.
Figure 10 is a stereoscopic view of the transition structure calculated using MINDO/3 for the reaction of methanol with a penicillin via an O-protonated pathway;
Figure 11 is a stereoscopic view of the transition structure for the reaction of methanol with penam via endo-attack;
Figure 12 is a stereoscopic view of the complexation of 5 to the peptide of Figure 1; and
Figure 13 is a stereoscopic view showing the
interaction of a cyclic structure with a model of a penicillin receptor.
Possible structures for peptides (e.g., enzymes),
penicillins and cephalosporins were examined using the computer program MMP2(85), which is available from the
Quantum Chemistry Program Exchange (QCPE) at the University of Indiana, Bloomington, Indiana, U.S.A. This program calculates the strain energy of a molecule in terms of the contributions to this energy associated with stretching of bonds, bending of bond angles, torsion about bonds, and electrostatic and van der Waals interactions of non-bonded atoms. To carry out the calculation, the Cartesian
coordinates of all atoms must be entered, and lists of connected and attached atoms defined. If the types of atoms present in the molecule of interest are known, the strain energy can be minimized by the application of the Newton-Raphson procedure to an unconstrained multivariable non-linear function that includes all of the individual
contributions noted above. This function is termed the force field. For the minimization to proceed in a reliable manner it is important that the geometry entered at the beginning of the calculation be reasonably accurate, and close to the bottom of an energy well.
For each different molecule to be examined with MMP2(85), it is first necessary to determine the parameters associated with the types of atoms present within this molecule. These parameters include, inter alia, standard bond lengths and bond angles, and stretching and bending force constants.
Bond lengths and angles are available from compilations of vibrational data, and others can be calculated by molecular orbital (MO) procedures. The general strategy for parameter development can be found in the monograph "Molecular
Mechanics", by U. Burkert and N. L. Allinger, published by the American Chemical Society, Washington, 1982. Since the parameters for peptides (e.g., enzymes), penicillins and
cephalosporins to establish the force field required
MMP2(85) were previously unknown, these were first
determined and tested for their ability to reproduce known experimental crystal structures, and known effects of solvent upon the conformations (three-dimensional
structures) of the different structural types. The
parameters are termed PEPCON (Appendix 1) (for peptides), PENCON (Appendix 2) (for penicillins), and CEPARAM (Appendix 3) (for cephalosporins). A second necessary requirement for the use of MMP2(85) is the provision of the initial set of Cartesian coordinates. For small molecules, such as penicillins and cephalosporins, the coordinates of an experimental crystal structure can be used. Minimization with the appropriate parameters then leads to a calculated structure that reproduces the
experimental structure. From this structure it is possible to proceed to other conformations and to the global minimum of the molecule by a series of dihedral drives around each of the dihedral angles of the molecule. This is an option available in MMP2(85), and it works well. However, such a strategy is impractical for the analysis of a peptide because of the very large number of dihedral angles that would have to be examined for any such molecule which contains more than two or three amino acid residues. Therefore, the computer programme ECEPP (Empirical
Conformational Energy Program for Peptides), which is available from QCPE, was modified to allow a random number generator to calculate the one-point energies of 200,000 initial structures containing permutations of the most probable backbone and dihedral angles. The fifty lowest
energy structures identified in this manner were read out, minimized using a quadratic minimization procedure, and then converted to MMP2(85) format for final minimization by the Newton-Raphson procedure. The objective of this initial search was to identify suitable starting parameters. This strategy has been tested extensively, works well, and has been applied to the treatment of a PBP, as described below.
More particulalry, in this procedure the strain energy of the molecule is minimized as a function of its dihedral angles with bond lengths and bond angles held constant. The minimization is preceded by a consideration of a subset of the parameters which form a basis for a specific subset of the complete parameter space, and the subset is comprised of the values 0, ±90, 180 degrees for the ∅ and
U dihedral angles of the backbone, and the values -60 and 180 degrees for the first dihedral angle of the side chains. The w dihedral angle and all other side chain dihedral angles are maintained at 180 degrees. Each of the infinite number of points in this parametric subspace corresponds to an
associated molecular strain energy. The subspace is then subjected to a sufficiently rich discrete randomly
distributed uniform mapping so that there is an arbitrarily large probability that, some points (r) are found in a convex neighbourhood of local energy minima, and this set of points (r) is then used for the initialization of the minimization procedure. A reasonable number of points for the randomly chosen discrete subset described above is 200,000 in the case of a polypeptide containing up to 10 amino acid
residues, and the set of points (r) preferably numbers 50. With these procedures in place, an initial series of nine penicillins (1a - 1i) was examined. Of these nine
compounds, 1a - 1d are highly active antibiotics widely used in medicine (ampicillin, syncillin, penicillin G, penicillin V) , 1e - 1f are significantly less active, and 1g - 1i are biologically inactive. The conformational analyses of these compounds revealed that antibacterial activity is associated specifically with a three dimensional structure in which the carboxyl group and side chain N-H project onto the convex face, and engage in hydrogen bonding lock-and-key
interactions with the receptor, i.e., the PBP.
1c: R = PhCH2CO-
1d: R = PhOCH2CO-
I
Next a conformational analysis was performed on the cephalosporins 2a - 2c. Each of these has the
phenoxyacetyl side chain, and can therefore be compared to penicillin V (1d). The ▲3-isomer 2a is biologically active, but undergoes a facile equilibration with the ▲2-isomer 2b, which is biologically inactive. The reason for the lack of activity of 2b has not previously been established, but it has been suggested that the 4-epi-▲2-isomer 2c would exhibit a better fit to the PBP receptor, and possess antibacterial activity. However, such compounds are also inactive. The reason for this lack of activity is, therefore, also unknown.
Each of 2a - 2c, like the penicillins 1a - 1d, is found to prefer a conformation in which the side chain N-H occupies the convex face of the molecule. As with the penicillins, it can thus be postulated that lock-and-key interactions with the receptor involve primary binding by the carboxyl group and this side chain N-H.
The active site serine D-alanyl carboxypeptidase- transpeptidase of Streptomyces R61 has been crystallized with incorporation of β-lactam compounds, and the crystal structure has been partially solved. The pH-dependence of the same enzyme has also been examined. Both kinds of studies suggest that the carboxyl group of a penicillin is closely associated with the protonated terminal amino group of the lysine residue of X-X-Lys. The crystal structure confirms that, in the complex, the β -lactam ring of penicillin is in close proximity to the active site serine. The pH-dependence study rules out
involvement of a histidine residue in the chemical process, in contrast to the behaviour of chymotrypsin and related serine proteases. This result means that the serine O-H participates in the chemical reaction with the substrate.
These observations suggest that a valid model of the active site of a PBP can be obtained in terms of the amino acids that surround the unique serine residue, i.e., in this case, Val-Gly-Ser-Val-Thr-Lys.
Accordingly, the peptide Ac-Val-Gly-Ser-Val-Thr-Lys-NH-CH3 was subjected to an ECEPP search of 200,000 initial structures, followed by MMP2(85) refinement of 50 low energy structures identified in this search. One low energy structure having the lysine and serine side chains in proximity was found. This structure is characterized by the set of dihedral angles summarized in Table 1, and is shown as Figure 1.
Table 1 Dihedral angles of the model of the active site of the PBP of Streptomyces R61
The structure of Figure 1 has several features of
interest. The convex face is mainly hydrophobic, and the concave face, which includes the serine and lysine side chains, is mainly hydrophilic. The concave face also contains the amide oxygen of the N-terminal acetyl group. These three sites are noted on Figure 1 as S (serine), L (lysine) and A (acetyl). The existence of a lock-and-key relationship between the concave face of Figure 1 and the previously determined convex face of penicillin and cephalosporin now seems clear. In terms of such a relationship, contact is required between the carboxyl group of the antibiotic and the terminal amino group of lysine, and also between the side chain N-H of the antibiotic and the acetyl oxygen.
The construction of a supermolecule in which the receptor is docked to a substrate through NH3+...-O2C and N-H...O=C hydrogen bonds is, therefore, desirable. To obtain the structure and energy of such a supermolecule using the program MMP2(85), it is necessary to devise a procedure for the generation of a starting set of Cartesian
coordinates.
A computer program has been written based on the
following approach to the problem. Let A refer to a receptor molecule containing N, atoms, and B a substrate molecule containing N2 atoms, which is to be docked to A.
It is assumed that the geometries of A and B are known in Cartesian or internal coordinates, and that
transformation between the two types of coordinate systems is possible. A start is thus made with (3N1-6) and (3N2-6) predetermined internal coordinates. To describe the geometry of the supermolecule containing (N1 + N2) atoms requires 3 (N1 + N2) - 6 internal coordinates, i.e., six new internal coordinates must be determined and minimized. These comprise, typically, one bond length, two bond angles, and three dihedral angles, and they may be termed "intermolecular" internal coordinates.
To use the computer program, for which the source code listing is given in Appendix 4, one of the desired hydrogen bonding interactions is selected, and its distance set at 1.7-2.5 Å, a typical intermolecular hydrogen bonding distance. Initial values are then given to the five remaining variables, and the energy is minimized, with the second hydrogen bond distance as a probe. The geometry of the resulting supermolecule, now expressed in Cartesian coordinates, is considered
appropriate for MMP2(85) minimization when the second hydrogen bond distance is 1.7-2.5 Å.
Figures 2-5 show stereoscopic views of the results of docking of the receptor model with, respectively,
penicillin V, ▲3-cephalosporin V, ▲2-cephalosporin V and 4-epi-▲2- cephalosporin V. It can be seen that, in each case, the serine O-H sits on the convex face of the β-lactam compound, in such a manner as to create a four-centred interaction between O-H and (O)C-N. This four-centred interaction is shown in closer detail for
penicillin V in Figure 6.
From the Cartesian coordinates of C-O-H and (O)N-C of the optimized complexes, it is possible to compute the root
mean square deviations (rms) in Å of the different four centred interactions, relative to a standard substrate, in this case penicillin V. When this is done for the series of penicillins 1a - 1i, it is found that all active penicillins have rms less than 0.2 Å, and all inactive penicillins have rms greater than 0.4 Å. For the series shown in Figures 2-5, the rms deviations are 0.000, 0.149, 0.338 and 0.148 Å.
This implies that the "fits" of the biologically active ▲3- cephalosporin and the biologically inactive 4-epi- ▲2-cephalosporin to the penicillin receptor are identical. The biologically inactive ▲2-cephalosporin has a poorer fit.
The biological activity of a drug depends not only on its ability to fit to a receptor, i.e., Step 1 of equation 1, but also on its ability to react chemically with the receptor, i.e., Step 2 of equation 1. The chemical reaction suggested by Figures 2-6 is a four centred process in which C7-O(Ser) (see A) and N-H(Ser) bond formation are concerted. This is an unprecedented chemical mechanism.
The hydrolysis and alcoholysis of β-lactam compounds has received much experimental and theoretical attention. In water above pH 8, the rate-determining step is addition to the carbonyl group to form a tetrahedral intermediate; below pH 6, there is rate-determining proton transfer to the β-lactam nitrogen, from the convex face of the molecule. Hydrolysis is extremely slow in the
biologically relevant pH range 6-8, and the possible existence of a molecular (four-centred) mechanism in this region has not been established. Likewise, all previous theoretical studies of β-lactam hydrolysis have
emphasized anionic addition to the β-lactam carbonyl group.
Molecular orbital (MO) calculations of the ab initio type represent an accepted and well established procedure for the probing of the mechanisms of chemical reactions.
Such calculations can be performed using low level (STO-3G) and high level (3-21G) basis sets using the computer programs GAUSSIAN 82 and GAUSSIAN 86, available from GAUSSIAN Inc., Pittsburgh, PA, U.S.A. Molecular orbital calculations of the semi-empirical type can be performed on relatively large molecular systems, and are valid once they have been calibrated with respect to an ab initio calculation on the same system. The semi empirical procedures AMI, MNDO and MINDO/3 are available in the computer program AMPAC, available from QCPE.
Table 2 summarizes the ab initio data (
, kcal/mol) for the reactions of N-methylazetidinone with water and with methanol via exo-oriented N- and O- protonated structures. For the hydrolysis reactions, the O-protonated structure is favoured by 1.75 kcal/mol at the lower STO-3G level (STO- 3G//STO-3G). One point
calculations at the more appropriate 3-21G level (3-21G//3-21G) increases the preference for the N-protonated transition structure to 5.66 kcal/mol. Analogous results are seen for methanolysis of N- methylazetidinone. These results prove that the four- centred interaction seen in Figures 2-6 reflects a genuine chemical process and, indeed, the energetically preferred chemical process.
The N- and O-protonated methanolysis transition
structures are shown in Figures 7 and 8, respectively.
Table 2 also summarizes the semi-empirical results for the hydrolysis and methanolysis of N-methylazetidinone, and it is evident that only MINDO/3 correctly reproduces
the preference for the N-protonated transition structure. Accordingly, MINDO/3 was used to examine the activation energies for the reactions of a large number of bicyclic azetidinones with methanol. These are summarized in Table 3.
Table 2
Relative
for the Hydrolysis and Methanolysis of N- Methylazetidinone via N- and O-Protonated Transition
Structures . a
Within each row of Table 3, the reactions of the
different structural types are compared to that of the parent penam ring system of penicillin, and the data are discussed row-by-row:
Table 3
Calculated
(kcal/mol, MINDO/3) relative to N- Methylazetidinone for the Methanolysis of β-Lactam
Compounds via Exo Formation of a Four-Centred N- Protonated Transition Structure
.
(1) the relative reactivities are carbapenam > penem > oxapenam > penam. Oxapenicillins and penems having the C3 and C6 substituents of penicillins are known to have antibacterial activity. Although the carbapenam ring system is known, carbapenicillins have not yet been prepared.
(2) in the comparison of the penam and cephem ring systems, the relative reactivities are penam > ▲3-cephem > ▲2-cephem, acetoxymethyl- ▲3-cephem. With a common acylamino side chain, penicillins are an order of
magnitude more active than acetoxymethyl-▲3-cephalosporins and the latter are, in general, an order of magnitude more active than 3-methyl-▲3-cephems; ▲2-cephems are inactive.
(3) introduction of the C3 -carboxyl group enhances the reactivity. It is believed that the carboxyl group assists the methanolysis through hydrogen bonding, because epimerization (C3β) decreases the reactivity significantly.
(4) introduction of C2-methyl substituents decreases the reactivity, unless a C3 -carboxyl group is present.
(5) the 6β-acylamino substituent has almost no effect on the reactivity. Consequently, the chemical reactivity of a penicillin differs only slightly from that of the parent penam. Figures 9 to 11 show, respectively, stereoscopic views of the N- and O-protonated transition structures for exomethanolysis of a penicillin- and O-protonated endomethanolysis of penam. Such endo-oriented transition structures are ca 1 kcal/mol higher in energy than the O-protonated exo-structures and 5-6 kcal/mol higher in energy than the N-protonated exo-structures.
Table 4 summarizes the "fits" of penicillin V and 2a - 2c mentioned above, as well as the "reactivities" of the different ring systems, as given by
for the reaction of methanol with the carboxylated substrates shown. The
product rms x
represents a combination of fit and reactivity, and is seen to order correctly the different classes of antibiotics in the order of their biological activities. Based on this quantity, 2b is inactive because of its poorer fit to the receptor, and 2c is inactive because of its decreased reactivity.
The difference between 2b and 2c can be compared to the differences seen in Row 3 of Table 3. That difference is attributed to facilitation of the chemical process by hydrogen bonding of the attacking alcohol to the carboxyl group when this group is on the convex face of the molecule. Thus 2c recovers the fit lost in 2b but concomitantly becomes less reactive. These
considerations suggest that the attachment of a hydrogen bonding donor substituent on the convex face of 2c will restore the chemical reactivity while retaining the acceptable fit to the receptor. Possible sites for the attachment of the required substituent are sulfur, C4 and C7 (see Table 4d for numbering). Attachment of F, CH3O and CH2OH to C4 and C7 in the required manner does not enhance the reactivity of 2c, but an alpha-oriented sulfoxide (3) exhibits reactivity superior to that of penicillin.
Although a malonic acid derivative which combines the favourable properties of 2b and 2c (4) exhibits somewhat reduced reactivity compared to penicillin (
= 3.51 kcal/mol), the product rms x ± is intermediate between
the active and inactive entries of Table 4. Accordingly, 3 and 4 are novel β-lactam containing structural types of potential biological interest. Table 4
Root Mean Square (rms) Difference (A) , relative to
Penicillin V, of the Cartesian Coordinates of the C-O-H
Atoms of Serine and the N-C=O atoms of the Azetidinone Ring in the Complexes of β-Lactam Compounds with a Model of the Penicillin Receptor; Activation Energies
(kcal/mol) for the Reaction of Azetidinones with
Methanol, relative to the Penam Nucleus; and the Product rms x
a Refers to MINDO/3 calculations on
b Refers to MINDO/3 calculations on
c Refers to MINDO/3 calculations on
d Refers to MINDO/3 calculations on
It is also possible to design entirely new structural types compatible with the combination of fit and
reactivity developed here. Based on the dihedral angles of penicillin V, a carboxyl group oriented so that it makes a dihedral angle of 150-160° with a "reactive site", and a hydrogen bonding donor such as N-H or O-H oriented so that it makes a dihedral angle of -150 to -160° with the "reactive site" is required. The reactive site should be one that reacts with methanol via a four-centred transition structure, and with E no greater than 3-4 kcal/mol higher than that for the reaction with an azetidinone.
Systematic calculation of activation energies has
identified
the imino moiety
as a functional group possessing the required reactivity, and incorporation of this moiety into a cyclic structure possessing dihedral angles of the required magnitude has identified structure 5 as a
candidate structure having antibacterial activity by a penicillin-cephalosporin mechanism. The result is shown in Figure 12.
EXAMPLE 1
Application of PEPCON to the Calculation of the
Polypeptide Crambin
This polypeptide contains 46 amino acid residues, 327 heavy atoms, and 636 atoms including hydrogens. The published crystal structure includes diffraction data refined to 1.5 Å. The Cartesian coordinates of the heavy (non-hydrogen) atoms of this crystal structure were used as input to MMP2(85), hydrogens were added using an option available in MMP2(85), and Newton-Raphson
minimization was performed using PEPCON. The calculated structure shows an rms deviation from the experimental structure of 0.291 Å for the heavy atoms of the backbone, and 0.310 Å for all heavy atoms. EXAMPLE 2
Application of PENCON to the Calculation of Penicillin V
Repetition of the experiment of Example 1, with the
Cartesian coordinates of the crystal structure of
penicillin V and the PENCON parameters leads to an rms deviation of 0.1 Å for all atoms.
EXAMPLE 3
Application of CEPARAM to the Calculation of
Cephalosporin The Cartesian coordinates of the crystal structure of a ▲2-cephalosporin having the phenoxyacetyl side chain were entered, and the energy was minimized using MMP2(85) in conjunction with the CEPARAM
parameters. The resulting rms deviation was 0.35 Å.
EXAMPLE 4
Application of the Random Number Strategy and ECEPP to the Conformational Analysis of a Peptide
The peptide Gly-Trp-Met-Asp-Phe-NH2 was entered into ECEPP, and an initial search was performed on 200,000 initial conformations of this molecule. The fifty lowest energy structures identified in this manner were
minimized in ECEPP using a quadratic minimization
procedure, and then refined using the PEPCON parameters of MMP2(85). One structure was strongly preferred, and the dihedral angles of this structure are identical to those of the gastrin tetrapeptide, which contains the Trp-Met-Asp-Phe-NH2 moiety of the above compound.
EXAMPLE 5 Calculation of the Structure of a Penicillin Receptor.
The peptide Ac-Val-Gly-Ser-Val-Thr-Lys-NHCH3 was treated as described in Example 4, and the fifty final structures were examined. Only one structure possessed lysine and serine side chains on the same side of the molecule.
This structure is shown in Figure 1, and its dihedral angles are summarized in Table 1.
EXAMPLE 6
Docking of Penicillin V to a Model of the Penicillin Receptor The receptor model of Example 5 was docked to penicillin V using the computer program of Appendix 4. Several conformations of the penicillin were examined, and the final lowest energy complex is shown in Figure 2
The compounds identified in this manner may thereafter be synthesized in accordance with standard chemical
procedures known to persons skilled in the art.
The invention will be further illustrated by way of the following specific examples of compounds that have been prepared:
EXAMPLE 7: Synthesis of 3-Carboxy-5-Hydroxymethyl-6, 6-Dimethyl-▲4-1, 4-Thiazine
In formula I, X = S; Y = OH; R1 = R2 = CH3, R3 = R4 = R5 = R6 = H. Both D- and L- configurations at C3 are prepared.
STEP 1
Methyl isopropyl ketone (15 mL, 140 mmoles) was added to a solution of potassium chloride (1.1 g, 14.8 mmoles) in water (9.6 mL). The mixture was stirred, warmed to 60 C, and illuminated with a 350 watt tungsten lamp mounted beside the flask. Bromine (11.9 g, 74.4 mmoles) was then added dropwise. When the colour of the first few drops had disappeared, the heating bath was replaced by a cold water bath, and the 350 watt bulb was replaced by a 60 watt bulb. Addition of bromine was continued at a rate sufficient to maintain the internal temperature at 40- 45ºC. When the addition was complete (25 min) the reaction mixture was allowed to stand for 2h and the organic phase was then separated, washed with water-
magnesium oxide and dried over anhydrous calcium chloride. Fractional distillation afforded 7 g of Al, b.p. 82-86°/145 torr. NMR (CDCl3) 2.36 (3H, s),
1.77 (6H, s).
STEP 2
The bromeketone Al (4.65 g, 28 mmoles) was dissolved in glacial acetic acid (40ml), and freshly recrystallized lead tetraacetate (12.5 g, 28.2 mmoles) was added. The mixture was heated at 100°C, with stirring, for 2 h and cooled to room temperature. Ethylene glycol (2 mL) was then added to destroy unreacted lead tetraacetate. The reaction mixture was diluted with ether (100 mL), washed successively with 10% sodium carbonate, water and saturated sodium chloride, dried and evaporated. The residue was distilled, and the fraction boiling at 57-60°C/120 torr was further purified by chromatography (silica gel, 5% > 10% -> 15% ether-hexane) to give the bromoketoacetate B1. NMR (CDCl3: 5.16 (2H, s), 2.13 (3H, s), 1.87 (6H, s).
STEP 3
Triethylamine (140 mL) was added to methylene chloride (3 mL). The solution was cooled to -20°C, and gaseous hydrogen sulfide was introduced during 10 min. Then the bromoketoacetate B1 (200 mg), in methylene chloride (1.0 mL), was added dropwise with stirring during 10 min. The yellow solution was diluted with methylene chloride (30 mL), washed successively with 2N hydrochloric acid, waterand saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to yield the
mercaptoketoacetate C1. NMR (CDCl3) 5.16 (2H, s), 2.18 (3H, s), 1.57 (6H, s), 1.55(1H, s) .
STEP 4
To triphenylphosphine (258 mg, 0.98 ramole) in dry tetrahydrofuran ( 1 .0 mL) , at -78°C under a nitrogen
atmosphere, was added dropwise with stirring a solution of dimethylacetylenedicarboxylate (144 mg, 0.99 mmole) in tetrahydrofuran (1.0 mL). The white slurry as maintained at -78°C for 10 min, and a solution of Boc-L (or D-)-serine (184 mg, 0.90 mole) in tetrahydrofuran (1.0 mL) was added dropwise. The temperature was maintained at - 78°C for 20 min and the reaction mixture was then allowed to warm to room temperature (2h). The solvent was removed and the residue was chromatographed on silica gel. Elution with 15% -> 22% -> 30% -> 35% ethyl
acetate-hexane afforded the beta-lactone D1. NMR (CDCl3) 5.29 (1H, br), 4.92 (1H, br), 4.34 (2H, br), 1.07 (9H, s).
STEP 5
To a solution of C1 (79.6 mg, 0.45 mmole) in dry degassed dimethylformamide (1.5 mL) was added dropwise a solution of lithium diisopropylamide (0.8 mmole) in
tetrahydrofuran (1.5 mL). The addition was carried out under nitrogen at -60°C. The reaction mixture was allowed to warm to -25°C during 50 min, cooled again to -55°C, and a solution of D1 (56.4 mg, 0.30 mmole) in dry degassed dimethylformamide (0.5 mL) was added dropwise. When the addition was complete, the mixture was warmed to -20°C,
stirred for 25 min and then diluted with ethyl acetate (30 mL) and washed with 0.5N hydrochloric acid (2 mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL) and the combined organic extracts were washed with water (2 x 5 mL) and saturated sodium chloride (1 x 5 mL), dried and evaporated. The oily residue was purified by preparative layer chromatography on a 10 x 20 cm plate coated with silica gel, using methylene chloride-ethyl acetate acetic acid (1.7:0.3:0.05) as eluant to give E1 (77 mg, 70.3%). NMR (CDCl3) 5.43 (1H, br), 5.20 (1H, d, 18 Hz), 5.04 (1H, d, 18 Hz), 4.46 (1H, br), 2.97 (1H, br), 2.78, 2.74 (1H, dd, 4.5, 9.0Hz), 2.17 (3H, s),
1.48(3H, s), 1.47 (3H, s), 1.44 (9H, s).
STEP 6
The acid E1 (77mg) was dissolved in methylene chloride (10 mL) and treated at 0°C with an ethereal solution of diazomethane. The solvent was removed and the residue was purified on a 5 x 10 cm silica gel plate using hexane-ethyl acetate (1.4:0.6) as eluant to give the ester F1 (48. 2 mg). NMR (CDCl
3) 5.32 (1H, br d), 5.15 (1H, d, 11Hz), 5.07 (1H, d, 11Hz), 4.48 (1H, br, q), 3.76 (3H, s), 2.91 (1H, q, 4, 12Hz), 2.74 (1H, q, 5.5, 12 Hz), 1.47 (6H, d), 1.44 (9H, s).
STEP 7
The ester Fl (46 mg), in tetrahydrofuran (1 mL) was treated at room temperature with 0.25 M lithium hydroxide (0.4 mL). After 25 min an additional 0.4mL of lithium hydroxide was added. The mixture was stirred for 35 min and then diluted with ethyl acetate (10 mL) and washed with 0.5 N hydrochloric acid (2 x 5 mL). The aqueous layer was extracted with ethyl acetate (2 x 5 mL) and the combined organic extracts were washed with water (1 x 5 mL), followed by saturated sodium chloride (1 x 5 mL), dried and evaporated. The residue was dissolved in the minimum of methylene chloride, treated with ethereal diazomethane, concentrated, and the residue was purified on a 10 x 20 cm silica gel plate. Elution with hexaneethyl acetate (1.4 : 0.6) gave Gl (14.4 mg). NMR (CDCl
3) 5.22 (1H, br), 4.58 (2H, d), 4.48 (1H, br), 3.75 (3H, s), 3.06 (1H, br), 2.92 (1H, br), 2.74 (1H, dd, 5, 11Hz), 1.46 (9H, s), 1.44 (6H, s).
STEP 8
To a solution of G1 (5 mg, 0.015 mmole) in freshly dried pyridine (0.2 mL) were added successively silver nitrate (3.4 mg, 0.02 mmole) and t-butyldiphenylchlorosilane (6.3 mg, 0.023 mmole). The solution was stirred for 15 min at room temperature under nitrogen. The solvent was then removed and the product was purified by preparative layer chromatography to give H1 (5.5 mg). NMR (CDCl3) 7.69 (4H, m), 7.41 (6H, m), 5.07 (1H, br), 4.70 (2H, s), 4.41 (1H, br), 3.72 (3H, s), 2.70 (1H, dd), 2.55(1H, dd), 1.43(9H, s), 1.28(3H, s), 1.26(3H, s), 1.10 (9H, s).
The silyated ester H1 (5 mg) was treated at room
temperature with formic acid (0.2 mL). After 33 min the reaction mixture was frozen and the solvent was removed by lyophilization to yield the enamine II. NMR
(CDCl3):7.69 (4H, m), 7.40 (6H, m), 5.90 (1H, s), 4.65 (1H, br), 3.79 (3H, s), 3.76 (1H, br), 3.17 (1H, dd, 10, 15Hz), 3.00(1H, dd,3,15 Hz), 1.49(3H, s), 1.31(3H, s), 1.08(9H, s).
STEP 10
The thiazine I1 was treated with lithium hydroxide, as described in Step 7, to remove the ester protecting group. The silylated protecting group was also removed in part to afford a reaction mixture which contained 3-carboxy-5-hydroxymethyl-6,6-dimethyl ▲4-1,4-thiazine.
EXAMPLE 8: Synthesis of 3-Carboxy-5-(2-Hydroxypropyl)-6,6-Dimethyl- ▲4-1,4-Thiazine
In formula II, X=S; Y=OH; R1=R2=CH3; R3=R4=R5=R6=H; R7=CH3. Both D- and L- configuration at C3 are prepared, but the R- and S- epimers at C8 have not been separated; the D-isomer is active.
STEP 1
A solution of ethyl 2-methylcyclopropanecarboxylate (5.0 g, 38.9 mmoles) in dry ether (5 mL) was added dropwise, with stirring under nitrogen, to the Grignard reagent prepared from magnesium turnings (1.935 g, 0.080 g-atom) and methyl iodide (12.43 g, 87.6 mmoles) in dry ether (42mL). The addition required 30 min; stirring was continued for 2.75 h at room temperature and then for 2 h under reflux. The reaction mixture was cooled in an ice- bath and saturated ammonium chloride (10mL) was added, with stirring. The layers were separated and the aqueous layer was extracted with ether (2 x 20mL). The combined organic phase was dried, evaporated and the residue distilled at 132-136°C to give the tertiary alcohol A2 (4.24 g, 95%)
STEP 2
To the alcohol A2 (4.24 g, 37 mmoles) cooled in an ice-bath, was added ice-cold 48% hydrobromic acid (15 mL). The mixture was shaken vigorously in the ice-bath for 30 min. The two layers were then separated, the aqueous layer extracted with hexane (2 x 20 mL), and the combined organic phase was washed successively with saturated bicarbonate (2 x 10 mL), water (2 x 10 mL) and saturated sodium chloride (2 x 10 mL), dried over anhydrous sodium sulfate, and evaporated. Distillation afforded 3.72 g (60%) of the bromide B2, b.p. 46-54°C/10 torr.
STEP 3
To a solution of the bromide B2 (3.72 g, 21 mmoles) in glacial acetic acid (20mL) was added potassium acetate (3.1g, 31.6 mmoles). The mixture was heated under reflux for 12 h, cooled, and poured into water (30mL).
Extraction with ether (3 x 30 mL), followed by successive
washing of the organic phase with saturated sodium carbonate, water and saturated sodium chloride, drying, and evaporation at room temperature yielded the acetate C2, 2.82 g (85%). NMR CDCl3) 5.10 (1H, brt), 4.88 (1H, q, 6Hz), 2.30 (1H, m), 2.19 (1H, m), 2.02 (3H, s), 1.71 (3H, br s), 1.62 (3H, br s), 8.00 (3H, d, 6Hz).
Step 4
The acetate C2 (320 mg, 2.05 mmoles) was dissolved in methanol (2mL) and treated dropwise with a 1.5 M solution of potassium hydroxide in methanol (1.38 mL). The reaction mixture was allowed to stand for 6h and was then neutralized with 1.5 M methanolic hydrogen chloride, and the solvent was removed. The residue was dissolved in methylene chloride, and this solution was washed
successively with water and saturated sodium chloride, dried and evaporated to give the alcohol D2 (208 mg, 99%).
The alcohol D2 (312 mg, 2.73 mmoles) was dissolved in dimethylformamide (2mL) and to this solution were added successively t-butyl dimethylchlorosilane (535mg, 3.55 mmoles). The mixture was stirred for 2h and then
filtered. The insoluble material was triturated with ether (20mL) and the combined organic material was washed successively with saturated sodium bicarbonate, water and saturated sodium chloride, dried and evaporated to give the silyated compound E2A (620 mg, 100%).
STEP 5B
The alcohol D2 (25mg, 0.22 mmole) was dissolved in dimethylformamide (0.2mL), and the solution was treated successively with pyridine (27 μl, 0.33 mole), t-butyldiphenylchlorosilane (90 μL, 0.35 mmole) and silver nitrate (56mg, 0.33 mmole). The mixture was stirred at room temperature for 4 h, and the product was then isolated, as described in Step 5A, to yield E2B.
STEP 6A
The olefin E2A (624mg, 2.73 mmoles) was dissolved in acetone (3mL) and 18-crown-6 (100mg, 0.27 mmole) and acetic acid (0.16mL) were added successively followed, dropwise, by a solution of potassium permanganate (603mg, 3.82 mmoles) in water (7.5mL). The mixture was stirred for 1 hr and then diluted with methylene chloride (50mL). The organic phase was washed successively with 20% sodium bisulfite, 0.5 N hydrochloric acid, saturated sodium bicarbonate, water and saturated sodium chloride, dried and evaporated. The residue was subjected to flash chromatography on silica gel (7g). Elution with 4 -> 15% ethyl acetate-hexane gave 479 mg (70%) of the ketol F2A.
The olefin E2B (77.5mg, 0.22 mole) was oxidized with potassium permanganate, as described in Step 6A, to yield the ketol F2B. NMR (CDCl3) : 7.72 (4H, m), 7.43 (6H, m),
4.43 (1H, q, 6Hz), 3.81 (1H,S), 2.81 (1H, dd, 5, 16Hz),
2.58 (1H, dd, 7, 16Hz), 1.31 (3H, s), 1.29 (3H, s), 1.10
(3H, d, 5Hz), 1.04 (9H, s)
STEP 7A
To a solution of the ketol F2A (478 mg, 1.83 mmoles) in methylene chloride (6mL) were added successively
triethylamine (0.76 mL, 4.0 mmoles) and methanesulfonyl chloride (0.24mL, 3.1 mmoles). The reaction mixture was stirred for 5h at room temperature and then diluted with methylene chloride (80mL). The solution was washed successively with water, 0.5 N hydrochloric acid,
saturated sodium bicarbonate, water and saturated sodium chloride, dried and evaporated. Flash chromatography on silica gel (3g) and elution with 7% -> 8% -> 9% -> 10% ethyl acetate-hexane gave G2A (432 mg, 70%).
STEP 7B
The ketol F2B (277mg, 0.72 mmole) was converted into the mesylate G2B (233mg), as described in Step 7A. NMR
(CDC13) 7.71 (4H, m), 7.41 (6H, m), 4.44 (1H, dd), 3.08 (3H, s), 2.95 (1H, dd, 6, 18Hz), 2.27 (1H, dd, 7, 18Hz), 1.63 (3H, s), 1.61 (3H, s), 1.15 (3H, d, 6Hz), 1.06 (9H, s )
STEP 8A
Methylene chloride (5mL) was saturated with hydrogen sulfide at -20°C, and triethylamine (0.14 mL, 1 mmole) and a solution of the mesylate G2A (233mg, 0.5 mmole) were added successively. The solution was stirred for 10 min at -20°C and for 45 min at -20°C -> 0°C, and was then diluted with methylene chloride (30mL), washed
successively with 0.5 N hydrochloric acid, water and
saturated sodium chloride, dried and evaporated to give, after drying at 0.1 torr, the mercaptan H2A (170mg, 85%). NMR(CDCl3) 4.37 (1H, m), 2.98 (1H, dd, 5, 11Hz), 2.63 (1H, dd, 4, 11Hz), 1.98 (1H, s), 1.49 (3H, s), 1.48 (3H, s), 1.17 (3H, d, 5Hz), 0.84 (9H, s), 0.05 (3H, s), 0.01 (3H, s)
STEP 8B
The mesylate G2B was converted into the mercaptan H2B as described in Step 8A. NMR (CDCl3) 7.71 (4H, m), 7.40 (6H, m), 3.00 (1H, dd, 6, 16Hz), 2.75 (1H, dd, 7, 16Hz), 1.93 (1H, s), 1.46 (3H, s), 1.45 (3H, s), 1.13 (3H, d, 6Hz), 1.05 (9H, s)
STEP 9
Under nitrogen, the raercaptan H2A ( 100mg, 0.36 mole ) was dissolved in degassed dimethylorraamide ( 1 .0 mL) . The
solution was cooled to -55°C and treated with 0.45mL of a solution of lithium diisopropylamide prepared from n-butyllithium (0.8mL of a 1.6M hexane solution) and diisopropylamine (0.36mL, 0.259g, 2.56 mmoles) in
degassed tetrahydrofuran (0.8mL). The reaction mixture was stirred at -45°C for 30 min, and a solution of the beta-lactone D1 (D- or L) (56.8mg, 0.30 mole) in degassed dimethylformamide (0.8mL) was added. The mixture was stirred at -30°C for 20 min and then diluted with
methylene chloride (10mL) and washed with 0.5N
hydrochloric acid. The aqueous layer was extracted with methylene chloride (2 x 5mL) and the combined organic extracts were washed with water, then saturated sodium chloride, dried and evaporated. The residue was dried under high vacuum and purified by flash chromatography (silica gel, 4g; 0% -> 8% ethyl acetate-methylene
chloride (1% acetic acid)) to give the coupled product I2D or I2L I2D (88.6%, [ ]D -2.27 (c 0.1, chloroform)). NMR (CDCl3) (one isomer) 5.28 (1H, br t), 4.48 (1H, br) 4.32 (1H, m), 2.83, 2.71 (2H, m), 2.71, 2.62 (2H, m),
1.44 (9H, s), 1.43 (6H, s), 1.16 (3H, d, 6Hz), 0.85 (9H, ), 0.05 (3H, s), 0.00 (3H, s). The nmr spectrum shows a 1:1 mixture of epimers in the 2-hydroxypropyl side chain.
I2L ( 83% , [ ] D +2 .33 (c 0. 1 , chloroform) ) . NMR (CDCl3) (one isomer) 5 .28 ( 1H, br t) , 4.48 ( 1H, br) , 4.32 ( 1H,
m), 2.86, 2.79 (2H, m), 2.70, 2.61 (2H, m), 1.43 (9H, s), 1.42 (6H, s), 1.16 (3H, d, 6Hz), 0.83 (9H,s), 0.04 (3H, s), 0.00 (3H, s). The nmr spectrum shows a 1:1 mixture of epimers in the 2-hydroxypropyl side chain.
STEP 10A
To I2D (22.7 mg, 0.049 mmole) was added formic acid
(0.3mL). The solution was shaken for 20min at room temperature and the solvent was then removed by
lyophilization. The residue was dissolved in a mixture of ether (3 mL) and water (lmL). The ether phase was extracted with water (lmL), and the combined aqueous phase was neutralized with 5% sodium bicarbonate and lyophilized to give 2 (5mg, 40%) having the D-configuration at C3, as a mixture of epimers in the 2-hydroxypropyl side chain. NMR (D20) 4.23 (1H, m), 3.80 (1H, m), 3.30 (1H, q), 2.70-2.85 (3H, m), 1.40 (6H, s), 1.15(3H, d).
STEP 10B
The procedure of Step 10A was repeated on 12L to give 2 having the L-configuration at C3
EXAMPLE 9 Bioassy of 2.-D
The compound was assayed for antibacterial activity on plates inoculated either with Sarcina lutea or
Escherichia coli. In the former case, penicillin G was employed as a standard. In the latter case, Cephalexin was employed as the standard. The compound was found to be 800 times less active than penicillin G, and 10 times less active than Cephalexin. The L-isomer of 2. was found to be inactive in both assays. EXAMPLE 10 Synthesis of 2-Thia-4-Carboxy-6-(2-Hydroxypropyl)-7,7-Dimethyl- 5-1,5-Thiazepine.
In formula III, X-Y = S-S; Z = OH; R1=R2=R7=CH3;
R3=R4=R5=R6. Both D- and L- configurations of C4 are prepared, but the R- and S - isomers at C9 have not been separated. The L-isomer is active (figure 13)
L-Cysteine hydrochloride (4.1mg, 0.026 mmole) was dissolved in 90% methanol-water (0.35mL), and a solution of the mercaptan H2A (Example 2, Step 8A) (7.1 mg, 0.026 mmole) in methanol (0.35mL) was added, followed by iodine (6.5mg, 0.026 mmole) and triethylamine (7 μL, 0.050 mmole). The reaction mixture was left for 30 min at room temperature and the solvent was then removed under reduced pressure. The residue was partitioned between pH 7 phosphate buffer (containing one drop of 10% sodium thiosulfate) and methylene chloride. The aqueous layer was extracted with ethyl acetate (1 x 5 mL) and
lyophilized. The residue was triturated with methanol, and the methanol extract was combined with the methylene chloride and ethyl acetate extracts and evaporated. The product was purified on a 10 x 15 cm alumina plate using methylene chloride-methanol-water (1.8 : 0.2 : 0.15) as eluant to give the disulfide A4-L (8.9mg, 80%). NMR (D
2O) : 4.19 (1H, m), 3.92 (1H, dd, 3.7 Hz), 3.18 (1H, m), 3.04 (1H, m), 2.92 (1H, m), 2.76 (1H, m), 1.43 (6H, s), 1.12 (3H, d, 7Hz). The compound is a mixture of epimers in the 2-hydroxypropyl chain.
Repetition of this experiment using D-cysteine in place of L-cysteine gave A4-D.
The acids A4-D and A4-L were dissolved in water
containing sodium bicarbonate and assayed for
antibacterial activity by plate assay using S. lutea. A zone of inhibition was observed with the L-isomer, but not with the D-isomer. The inhibition is ascribed to the formation of the cyclic structure 3L, whose interaction with the model of the penicillin receptor is shown in Figure 13.
EXAMPLE 11: Synthesis of 3-Carboxy-5-Oximino-1,4-Thiazine In formula IV, X=S; R1= R2=H; R3=R4=R9=H; X=N; Z =OH.
Both D- and L- isomers are described.
STEP 1
To a solution of D-cysteine (605.8mg, 5 mmoles) in methanol (10mL) were added successively ethyl
bromoacetate (0.99g, 5.95 mmoles) and triethylamine
(1.4mL, 1.02g, 10 mmoles). The solution was stirred for 20 min at room temperature and ether (20mL) was then added. The product was collected by filtration, washed with ether and dried. Five hundred mg of this material were suspended in dimethylformamide (5mL), and p- toluenesulfonic acid (458mg, 2.41 mmoles) was added. The resulting solution was treated portionwise with
diphenyldiazomethane until the color of the diazo
compound persisted, and the reaction mixture was stirred overnight. It was then diluted with ether (20mL) and extracted with water (2 x 10mL). The aqueous extract was made alkaline by addition of saturated sodium carbonate, and was then extracted with ethyl acetate (3 x 10mL). The combined organic extracts were washed with water and saturated sodium chloride, dried and evaporated. A 370- mg portion of the residue (0.99 mmole) was dissolved in 1,4-dioxane (8mL), 2-pyridone (47 mg, 0.49 mole) was added, and the solution was heated under nitrogen at 102°C for 7 h. Additional 2-pyridone (23.5 mg, 0.25 mmole) was then added and heating was continued for 4 h. At this time the solvent was removed under reduced
pressure and the residue was purified on 15 g of silica gel. Elution with 8% ethyl acetate-hexane afforded 252 mg (78%) of the thiazinone benzhydryl ester A5-D. NMR (CDCl3) 7.34 (10H, m), 6.96 (1H, s), 6.48 (1H, s), 4.46 (1H, m), 3.33 (2H, s), 3.21 (1H, dd, 4, 15Hz), 2.98 (1H, dd, 9, 15Hz).
STEP 2
The thiazinone ester A5-D (252 mg, 0.77 mmole) was dissolved in dry tetrahydrofuran (5mL) under nitrogen, and the reagent prepared from phosphorous pentasulfide and diphenyl ether according to Tetrahedron Letters 3815 (1983) (244mg, 0.46 mole) was added. The solution was stirred for 35 min, concentrated, and the residue was purified on silica gel (8g). Elution with 15% ethyl acetate-hexane afforded 214 mg (81%) of the thioamide B5- D. NMR (CDCl3) 8.59 (1H, s), 7.35 (10H, m), 6.98 (1H, s), 4.39 (1H, m), 3.79 (2H, s), 3.32 (1H, dd, 4, 15Hz), 3.02 (1H, dd, 8, 15Hz).
STEP 3
The thioamide B5-D (80mg, 0.23 mmole) was dissolved with stirring in ice-cold dry tetrahydrofuran (92mL) under nitrogen and sodium hydride (80%, 8.4mg, 0.28 mmole) was added. After 5 min stirring in an ice-bath, the reaction mixture was treated with 30 μL (0.48 mmole) of methyl iodide. Reaction was complete after 25 min. Dilution with ether, followed by successive extraction with water, saturated sodium bicarbonate and saturated sodium
chloride, drying and evaporation gave a product which was purified on silica gel (3g). Elution with 10% ethyl acetate-hexane afforded 59.1mg (75%) of the
thiomethylimine C5-D. NMR (CDCl
3) 7.35 (10H, m), 6.96 (1H, s), 4.53 (1H, m), 3.27 (1H, dd, 5, 18Hz), 3.15 (1H, dd, 5, 18Hz), 2.99 (1H, dd, 3, 13Hz), 2.81 (1H, dd, 4, 13Hz), 2.37 (3H, s).
STEP 4
The thiomethylimine C5-D (59 mg, 0.165 mole) was
dissolved in tetrahydrofuran (0.5mL) and added to a solution prepared under nitrogen from hydroxylamine hydrochloride (68.8mg, 0.99 mmole) and 1.65 M methanolic sodium methylate (0.3 mL, 0.5 mmole) in methanol (0.7mL). The reaction was complete in 10 min. The mixture was diluted with methylene chloride (10mL), washed
successively with saturated sodium bicarbonate, water and saturated sodium chloride, dried and evaporated.
Chromatography on silica gel (1.5g) and elution with 12% ethyl acetate-methylene chloride gave 52.7 mg (94%) of the oximino ester D5-D. NMR (CDCl3) 7.34 (11H, m), 6.93. (1H, s), 5.97 (1H, s), 4.28 (1H, m), 3.30 (1H, d, 13Hz), 3.21 (1H, dd, 3, 13Hz), 3.16 (1H, d, 13Hz), 3.08 (1H, dd, 7, 13Hz).
STEP 5
The ester D5-D (47 mg) was dissolved in formic acid
(lmL). After 5h at room temperature the reaction mixture was frozen and the solvent removed by lyophilization.
The residue was partitioned between ether and water, the ether layer was extracted once with water, and the combined aqueous extracts were lyophilized again to yield 4-D. NMR (D2O) : 4.15 (1H, m), 3.50 (1H, d, 14Hz), 3.34 (1H, d, 14Hz), 3.15 (1H, dd, 6, 15Hz), 3.02 (1H, dd, 6,
15 Hz)
The L-enantioraer of 4 was prepared as described above, but starting with L-cysteine in place of D-cysteine .
Antibacterial activity was observed on the D-isomer.
EXAMPLE 12: Synthesis of 3D-Carboxy-5-Phenylacetylhydrazil-▲4-Thiazine.
A solution of thiomethylimine C5-D (11 mg, 0.031 mmole) and phenylacetic hydrazide (9.2 mg, 0.062 mmole) was stirred overnight under nitrogen in methylene chloride (0.6 mL). The reaction mixture was purified by
preparative layer chromatography on silica gel to give the adduct P (14mg, 98%). NMR (CDCL3): 7.34 (1H, m), 6.89 (1H, s), 6.55 (1H, br s), 4.24 (1H, br s), 3.78 (2H, s) 3.55 (1H, br, s), 3.33 (1H, d, 15 Hz), 3.17 (1H, d, 15 Hz), 3.05 (2H, br).
The adduct P (10 mg, 0.022 mmole) was treated with formic acid (0.4 mL). The solution was allowed to stand at room temperature for 5 h and the solvent was then removed by lyophilization. The residue was partitioned between ether (0.2 mL) and water (0.2 mL). The ether layer was extracted once with water (0.2 mL), and then the combined aqueous phase was freeze dried to give the product Q. (3 mg, 47%). NMR (D
2O, NaHCO
3) : 8.33 (1H, s), 7.28 (5H, m), 3.98 (1H, m), 3.55 (2H, s) 3.35 (1H, d, 17.5 Hz), 3.12 (1H, d, 17.5 Hz), 3.11 (1H, br d, 15 Hz), 2.83 (1H, br d, 15 Hz), 2.83 (1H, s).
The L-isomer QL was prepared in the same way, starting with C5-L.
PEPCON
159 39 9 123 39 78.50
5 6 1 5 0.00 0.00 0.30
5 3 9 1 0.00 15.00 0.00
3 9 1 6 0.00 0.00 0.00
9 1 6 5- 2.50 3.00 -1.00
6 1 9 14 0.00 0.00 0.00
1 1 1 1 0.20 0.27 0.09
1 1 1 3 0.26 0.00 0.06
1 1 1 5 0.00 0.00 0.27
1 1 1 8 0.00 0.00 0.06
1 1 1 9 0.00 0.00 0.06
1 1 1 13 0.00 0.00 0.40
1 1 1 15 0.00 0.00 0.80
1 1 1 19 0.00 0.00 0.60
1 1 2 2 0.00 0.00 0.10
1 1 3 7 0.00 0.00 -0.04
1 1 3 9 0.00 0.00 -0.04
1 1 3 11 0.00 0.00 -0.09
1 1 3 12 0.00 0.00 -0.20
1 1 4 4 0.00 0.00 0.10
1 1 4 26 0.00 0.00 0.10
1 1 4 27 0.00 0.00 0.10
1 1 6 21 0.00 0.00 0.30
1 1 8 23 0.00 0.00 0.30
1 1 9 1 0.00 0.00 0.12
1 1 9 3 0.00 0.00 0.06
1 1 9 14 0.00 0.00 0.06
1 1 13 23 0.00 0.00 0.20
1 1 15 1 0.00 0.00 0.70
1 1 15 15 0.00 0.00 0.80
1 1 15 25 0.00 0.00 0.20
1 1 19 2 0.00 0.00 0.05
1 1 19 23 0.00 0.00 0.05
1 2 2 2 0.00 3.50 0.00
1 2 2 5 0.00 3.50 0.00
1 3 9 1 1.80 6.49 0.00
1 3 9 1 1.80 19.00 0.00
1 3 9 14 0.00 2.66 0.00
1 3 12 24 0.60 0.00 3.20
1 4 4 5-0.30 3.80 0.00
1 4 4 26 0.00 3.50 0.00
1 4 26 4 0.00 5.00 0.00
1 4 26 23 0.00 5.00 0.00
1 4 27 2-0.30 3.80 0.00
1 4 27 27 0.00 3.50 0.00
1 9 1 3 0.00 0.00 0.12
1 9 1 5 0.00 0.00 0.12
1 9 3 7 0.00 7.19 0.00
1 15 1 5 0.00 0.00 0.70
1 15 15 1 0.00 -7.60 1.70
1 19 2 8 0.00 4.50 0.00 1 19 2 19 0.00 4.50 0.00 2 1 1 3 0.26 0.00 0.06 2 1 1 5 0.00 0.00 0.27 2 1 1 8 0.00 0.00 0.06 2 1 1 9 0.00 0.00 0.06 2 1 1 13 0.00 0.00 0.06 2 1 3 7 0.00 0.00 -0.35 2 1 3 9 0.00 -0.50 -1.70 2 2 1 3 0.00 0.00 0.90 2 2 1 5 0.00 0.00 0.05 2 2 2 2- 0. 30 3.80 0.00 2 2 2 5 0.00 3.50 0.00 2 2 2 6 0.00 3.80 0.00 2 2 2 27 -0 .30 3 . 80 0. 00 2 2 6 21 0.00 1.80 0.00 2 2 27 4 0.00 3.50 0.00 2 2 27 26 0.00 3.50 0.00 2 2 27 27-0.30 3.80 0.00 2 19 1 5 0.00 0.00 0.05 2 27 4 4 0.00 3.50 0.00 2 27 26 4 0.00 5.00 0.00 2 27 26 23 0.00 5.00 0.00 2 27 27 2- 0.30 3.80 0.00 2 27 27 4 0.00 3.50 0.00 2 27 27 26 0.00 3.50 0.00 3 1 1 3 0.26 0.00 0.06 3 1 1 4 0.26 0.00 0.06 3 1 1 5 0.00 0.00 0.16 3 1 1 6 0.26 0.00 0.06 3 1 1 8 0.00 0.00 0.06 3 1 1 9 0.00 0.00 0.08 3 1 1 13 0.00 0.00 0.06 3 1 1 15 0.26 0.00 0.06 3 1 8 23 0.00 0.00 0.303 1 9 3 0.00 0.00 0.06 3 1 9 14 0.00 0.00 0.06 3 1 13 23 0.00 0.00 0.30 3 9 1 5 0.00 0.00 0.064 1 1 5 0.00 0.00 0.274 1 1 8 0.00 0.00 0.06 4 1 1 9 0.00 0.00 0.06 4 1 1 13 0.00 0.00 0.06 4 44 1 5 0.00 0.00 0.104 44 26 4 0.00 5.00 0.00 4 44 26 23 0.00 5.00 0.004 4 4 26 27 0.00 5.00 0.004 44 27 27- 0.30 3.80 0.004 26 4 5 0.00 5.00 0.004 26 4 26 0.00 5.00 0.004 26 27 27 0.00 5.00 0.004 27 2 5- 0. 30 3.80 0.00 4 27 27 26- 0 .30 3.80 0.005 1 1 5 0.00 0.00 0.24
5 1 1 6 0.00 0.00 0.50 5 1 1 8 0.00 0.49 0.16 5 1 1 9 0.00 0.49 0.16 5 1 1 13 0.00 0.00 0.40 5 1 1 15 0.00 0.00 0.40 5 1 1 19 0.00 0.00 0.30 5 1 3 7 0.00 0.00 -0.04 5 1 3 9 0.00 0.00 -0.04 5 1 3 11 0.00 0.00 -0.09 5 1 3 12 0.00 0.00 -0.06 5 1 4 26 0.00 0.00 0.10 5 1 4 27 0.00 0.00 0.10 5 1 6 21 0.00 0.00 0.30 5 1 8 23 0.00 0.00 0.30 5 1 9 14 0.00 0.00 0.06 5 1 13 23 0.00 0.00 0.20 5 1 15 15 0.00 0.00 0.80 5 1 15 25 0.00 0.00 0.50 5 1 19 23 0.00 0.00 0.05 5 2 2 5- 0.30 3.80 0.00 5 2 2 6- 0.30 3.80 0.00 5 2 2 27 0.00 3.50 0.00 5 2 27 26 0.00 3.50 0.00 5 2 27 27 0.00 3.50 0.00 5 3 9 14 0.00 2.33 0.0 5 4 4 26 0.00 3.50 0.00 5 4 4 27 0.00 3.50 0.00 5 4 26 23 0.00 5.00 0.00 5 4 26 27 0.00 5.00 0.00 6 1 1 8 0.00 0.00 0.06 6 1 1 9 0.00 0.00 0.06 6 1 1 13 0.00 0.00 0.06 7 3 1 8 0.00 0.00 -0.04 7 3 1 9 0.00 0.00 -0.04 7 3 1 13 0.00 0.00 -0.04 7 3 9 14 0.00 2.66 0.00 7 3 12 24 0.00 0.00 3.10 8 1 1 15 0.00 0.00 0.06 8 1 3 9 0.00 0.00 -0.09 8 1 3 11 0.00 0.00 -0.09 8 1 3 12 0.00 0.00 -0.06 9 1 1 15 0.00 0.00 0.06 9 1 3 9 0.00 0.00 -0.04 9 1 3 11 0.00 0.00 -0.09 9 1 3 12 0.00 0.00 -0.06 9 3 1 13 0.00 0.00 -0.0611 3 1 13 0.00 0.00 -0.0912 3 1 13 0.00 0.00 -0.06 13 1 1 15 0.15 0.00 0.1019 2 19 23 0.00 4.50 0.00 19 2 8 23 0.00 4.50 0.00 23 19 2 8 0.00 4.50 0.00 23 26 4 26 0.00 5.00 0.0023 26 27 27 0.00 5.00 0.00
26 4 4 26-0 30 3.80 0.0026 4 4 27 0 00 3.80 0.0 1 1 4.40 1.525 1.510
1 2 4.48 1.504
1 3 4.75 1.526
1 4 4.40 1.504
1 5 4.60 1.081
1 6 5.36 1.425
1 8 5.10 1.461
1 9 5.47 1.452
1 13 5.15 1.472
1 15 3.21 1.815
1 19 5.27 1.460
5 6 4.60 0.968
2 2 9.60 1.382
2 5 4.60 1.101
2 6 6.20 1.381
2 8 5.10 1.331
2 19 5.10 1.331
2 27 6.51 1.400
3 5 4.8 1.103
3 6 5.05 1.330
3 7 10.01 1.229
3 9 7.74 1.330
3 11 5.11 1.250
3 12 5.05 1.328
6 21 4.60 0.968
4 4 7.19 1.371
4 5 4.60 1.101
4 26 5.69 1.394
4 27 5.39 1.459
8 23 6.10 1.015
9 14 5.78 0.991
12 24 7.20 0.972
13 23 6.03 1.023
15 15 3.10 2.024
15 25 3.80 1.354
19 23 5.95 1.007
23 26 6.05 1.010
26 27 5.94 1.380
27 27 6.21 1.419
1 1 0.000
1 2 0.100
1 3 -1.020
1 4 -0.180
1 5 0.000
1 6 2.530
1 8 3.980
1 9 2.650
5 6 -1.960
1 13 1.720
1 15 -0.671
1 19 2.058
2 2 0.000
2 5 -0.058
2 6 0.810
2 8 4.524
2 19 3.260
2 27 -0.700
3 5 0.0
3 6 0.000
3 7 3.010
3 9 3.320
3 11 3.950
3 12 1.850
6 21 -1.960
4 4 0.000
4 5 0.000
4 26 2.120
4 27 1.120
8 23 -1.410
9 14 -1.810
12 24 0.000
13 23. -1.350
15 15 0.000
15 25 0.000
19 23 -2.270
23 26 1.430
26 27 -1.030
27 27 0.000
4 0.044 1.940
11 0.066 1.780
12 0.050 1.740
13 0.030 1.900
14 0.017 0.930
19 0.055 1.820
5 0.036 1.250
6 0.055 1.820
7 0.044 1.940
1 1 1 0.45 110.30 1 1 1 1 0.45 111.20 2 1 1 1 0.45 112.40 3 1 1 2 0.58 114.00
1 1 3 0.67 107.80 1 1 1 3 0.67 110.80 2 1 1 3 0.67 112.20 3 1 1 4 0.71 113.10
1 1 5 0.36 109.39
1 1 6 0.56 109.10 1 1 1 6 0.56 104.10 2 1 1 6 0.56 109.40 3 1 1 8 0.57 109.47
1 1 9 0.56 109.40 1 1 1 9 0.56 109.60 2 1 1 9 0.85 111.10 3 1 1 13 0.90 111.20
1 1 15 0.63 108.80
1 1 19 0.75 111.20
1 2 2 0.55 121.40
1 2 5 0.36 118.20
1 3 7 0.86 120.60
1 3 9 0.78 116.40
1 3 11 0.64 117.00
1 3 12 0.70 115.00
1 4 4 0.80 129.80
1 4 26 0.80 121.70
1 4 27 0.80 128.60
1 6 21 0.35 108.40
1 8 23 0.48 109.50
1 9 1 0.45 111.90
1 9 2 0.75 123.20
1 9 3 0.49 120.60 11 9 3 0.35 121.70 2 1 9 14 0.54 124.00
1 13 23 0.40 109.50
1 15 1 0.78 97.60
1 15 15 1.17 103.90
1 15 25 0.48 96.00
1 19 2 0.56 123.20
1 19 23 0.38 118.40
2 1 3 0.47 110.2
2 1 5 0.36 109.40
2 2 2 0.43 120.00
2 2 5 0.36 120.00
2 2 6 0.75 121.00
2 2 27 0.96 120.00
2 6 21 0.35 113.00
2 8 23 0.50 120.00
2 9 23 0.50 120.00
2 19 23 0.38 120.00
2 27 4 0.90 134.90
2 27 26 0.35 132.80
2 27 27 0.90 122.70
3 1 5 0.37 107.90
3 1 8 0.82 110.74
3 1 9 0.44 110.00 13 1 9 0.47 109.70 2 3 1 9 0.56 110.80 33 1 13 0.90 110.74
3 9 14 0.50 122.50
3 12 24 0.74 106.10
4 1 5 0.38 109.50
4 4 5 0.36 126.30
4 4 26 0.80 107.90
4 4 27 0.43 106.40
4 26 4 0.80 106.30
4 26 23 0.40 126.40
4 26 27 0.80 111.60
4 27 27 0.95 108.80
5 1 5 0.32 109.40
5 1 6 0.43 103.10
5 1 8 0.46 108.80
5 1 9 0.36 109.39 1 5 1 9 0.36 109.41 2 5 1 9 0.36 110.00 3 5 1 13 0.50 108.80
5 1 15 0.36 112.00
5 1 19 0.38 109.00
5 2 27 0.36 120.00
5 3 7 0.37 112.0
5 3 9 0.40 122.3
5 4 26 0.36 120.00
7 3 9 0.85 124.10
7 3 12 1.13 124.50
8 2 19 0.80 120.00
11 3 11 0.85 126.00
14 9 14 0.50 120.00
19 2 19 0.80 120.00
23 8 23 0.50 106.80
23 19 23 0.50 120.00
23 13 23 0.50 109.50
23 26 27 0.40 124.20
26 4 26 0.90 110.90
26 27 27 0.90 104.40
1 6 5 0.35 108.40
9 1 6 0.62 111.00
3 11 0.8
3 12 0.8
9 14 0.05
2 27 0.05
2 1 0.05 A
2 2 0.05
2 5 0.05
2 6 0.05
2 8 0.05
2 19 0.05
3 1 0.8
3 5 0.8
3 7 0.8
3 9 0.8
9 1 0.05
9 3 0.05
4 26 0.05
4 4 0.05
27 27 0.05
27 2 0.05
27 4 0.05
26 27 0.05
4 1 0.05
4 5 0.05
4 27 0.05
27 26 0.05
APPENDIX 2
PENCON
117 25 6 70 25
1 1 3 6 0.40 -0.30 -0.07 1 3 9 20 1.80 6.49 -6.23 1 6 2 2 3.53 2.30 -2.53 1 6 3 7-1.66 8.98 0.00 1 6 3 16-2.50 1.39 0.00 1 8 20 5 0.00 0.00 0.52 1 8 20 22-0.20 0.73 0.80 1 8 20 26 0.00 0.00 0.00 1 16 1 5 0.00 0.00 0.27 1 16 15 22-1.00 3.01 1.86 1 16 16 3-0.26 1.00 -0.80 1 16 16 5 0.00 0.00 -0.90 1 16 16 27-0.26 0.70 -0.06 1 25 6 19 0.00 0.00 0.00 1 25 25 25 0.00 3.50 0.00
2 1 3 9 0.00 -0.50 -1.70
2 2 1 3 0.00 0.00 0.50
2 2 2 6 0.00 3.80 0.00
2 2 2 25-0.30 3.50 0.00
2 2 25 19 0.00 1.00 0.30
2 2 25 25 0.00 1.00 0.30
2 6 1 3 0.00 0.00 -0.60
2 6 1 5 0.00 0.00 0.53
2 25 19 6 0.00 4.50 0.00
2 25 25 3 0.00 3.50 0.00
3 6 1 6-1.00 -5.00 0.00
3 9 20 5 0.00 0.00 0.51
3 9 20 22 0.00 0.00 0.01
3 9 20 26-3.50 -0.05 -4.30
3 16 16 15-1.75 0.60 1.50
3 16 27 22-1.00 -0.80 0.40
3 16 27 26-1.00 -0.53 1.13
3 25 25 1 0.00 5.00 0.00
3 25 25 6 0.00 3.80 0.00
3 25 25 19 0.00 3.80 0.00
5 1 16 15 0.00 0.00 0.40
5 1 16 16 0.00 0.00 0.27
5 1 25 6 0.00 0.00 0.54
5 1 25 25 0.00 0.00 0.05
5 2 2 6-0.30 3.80 0.00
5 2 2 25 0.00 3.50 0.00
5 16 3 6 0.00 0.00 -0.02
5 16 3 7 0.00 0.00 -0.04
5 16 3 29 0.00 0.00 -0.04
5 16 3 30 0.00 0.00 -0.09
5 16 16 15 0.00 0.00 -0.80
5 16 27 22 0.00 0.00 0.40
5 16 27 26 0.00 0.00 0.04
5 20 22 5 0.00 0.00 1.30 5 20 22 15 0.00 0.00 0.04 5 20 22 27 0.00 0.00 0.10 5 20 26 27 0.00 0.00 -0.09 5 20 26 28 0.00 0.00 0.21 5 22 15 16 0.00 0.00 0.00 5 22 20 8 0.00 0.00 0.20 5 22 20 9 0.00 0.00 0.20 5 22 20 12 0.00 3.00 0.40 5 22 20 13 0.00 5.00 0.20 5 22 20 26 0.00 0.00 0.87 5 22 27 16 0.00 0.00 0.00 5 22 27 26 0.00 0.00 0.98 6 1 3 7 0.00 0.00 -0.04 6 1 3 9 0.00 0.00 -0.04 6 3 16 16 0.40 -0.30 -0.07 6 3 16 27 0.00 0.00 0.50 6 19 25 25 0.00 4.50 0.00 6 25 25 25 0.00 3.80 0.00 7 3 9 20 0.00 7.19 0.00 7 3 16 16 0.00 0.00 -0.04 7 3 16 27 0.00 0.00 -0.04 7 3 25 25 4.00 0.40 2.40 9 3 25 25 4.30 0.40 2.90 8 20 22 27 0.00 0.00 0.40 8 20 26 27 -4.30 5.00 -1.50 8 20 26 28 -3.50 3.00 8.00 9 20 22 15 0.50 0.00 1.00 9 20 22 27 0.00 0.00 0.40 9 20 26 27 -4.30 5.00 -1.50 9 20 26 28 -3.50 3.00 8.0012 20 22 15 0.00 0.00 0.0412 20 22 27 0.00 0.00 0.5012 20 26 27 0.00 0.00 -0.09 12 20 26 28 0.00 0.00 0.21 13 20 22 15 0.50 -2.75 3.00 13 20 22 27 0.00 0.00 1.4013 20 26 27 -4.30 5.00 -1.50 13 20 26 28 -1.50 5.00 8.0014 9 3 25 0.00 2.66 0.00 14 9 20 22 0.00 0.00 0.01 14 9 20 26 0.00 0.00 0.01 15 16 16 27 -0.75 2.00 -0.90 15 22 20 26 0.00 1.00 1.00 15 22 27 16 -3.00 7.00 0.00 15 22 27 26 0.00 1.00 0.30 16 15 22 20 -2.50 3 .60 -3.00 16 15 22 27 -2.50 3 . 00 -1. 00 16 16 3 29 0.00 0.00 -0.20 16 16 3 30 0.00 0.00 -0.09 16 16 15 22 0.00 2.50 0.40 16 16 27 22 -1.00 -2 .50 0.40 16 16 27 26 -0.50 0 .50 2.50 16 27 22 20 0.00 1.00 -0.50
16 27 26 20 -4.00 3.00 0.40
16 27 26 28 -1 .00 3.00 2.00
19 6 25 25 0 .00 3.50 0.00
19 25 25 25 0 .00 3.80 0.00
20 9 3 25 1 .80 6.49 -5.234 20 22 27 26 1 .50 10.00 1.004 20 26 27 22 -1 .00 8.50 5.00 4 22 20 26 27 -1 .00 9.00 3.00
22 20 26 28 0 .20 3.50 -2.50
22 27 26 28 0 .20 8.00 -4.70
25 6 19 25 0 .00 3.50 0.00 4 26 20 22 27 -2 .65 6.10 0.20
27 16 3 29 0 .00 0.00 -0.06
27 16 3 30 0 .00 0.00 -0.09
1 16 5.26 1.525
1 25 4.48 1.512
2 25 9.60 1.526
3 16 4.45 1.550
3 25 9.60 1.332
5 16 4.60 1.070
5 20 4.39 1.080
5 22 4.38 1.090
6 19 4.32 1.410
6 25 4.09 1.350
8 20 5.10 1.510
9 20 5.47 1.449
12 20 3.23 1.793
13 20 2.30 1.926
15 16 3.98 1.851
15 22 3.98 1.810
16 16 4.50 1.565
16 27 4.30 1.476
19 25 6.50 1.310
20 22 2.56 1.553
20 26 2.58 1.527
22 27 4.30 1.484
25 25 5.83 1.380
26 27 4.79 1.393
26 28 8.65 1.201
1 16 0.000
1 25 0.100
2 25 0.000
3 16 5.872
3 25 0.000
5 16 0.000
5 20 0.000
5 22 0.000
6 19 0.081
6 25 0.212
8 20 3.980
9 20 0.000
12 20 1.940
13 20 1.790
15 16 4.464
15 22 3.653
16 16 0 .000
16 27 2 .304
19 25 0 .330
25 25 0.000
20 22 -0 .062
20 26 1 .547
22 27 0 .712
26 27 2 .280
26 28 1 .533
16 0. 044 1 .920
20 0. 044 1 .920
25 0. 044 1 .920
26 0. 044 1 .920
27 0. 055 1 .820
28 0. 066 1 .740
1 6 2 0.77 117.00
1 8 20 0.63 110.00
1 16 1 0.45 110.90 1 1 16 1 0.45 111.20 2 1 16 1 0.45 112.40 3 1 16 5 0.36 109.40
1 16 15 0.63 109.80
1 16 16 0.45 110.30 1 1 16 16 0.45 111.20 2 1 16 16 0.45 112.40 3 1 25 6 0.50 117.00
1 25 25 0.55 134.00
2 2 25 0.43 120.00
2 25 19 0.43 120.00
2 25 25 0.43 128.00
3 1 6 0.70 106.00
3 9 20 0.49 121.20
3 16 5 0.37 107.90
3 16 16 0.67 113.90
3 16 27 0.44 111.30
3 25 25 0.60 129.00
5 1 16 0.36 109.40
5 1 25 0.36 109.40
5 16 15 0.36 112.00
5 16 16 0.36 113.36
5 16 27 0.50 100.00
5 20 8 0.36 98.90
5 20 9 0.36 98.90
5 20 22 0.33 113.50
5 20 26 0.63 113.50
5 22 15 0.36 112.00
5 22 20 0.45 119.30
5 22 27 0.37 112.40
6 3 16 0.65 107.10
6 19 25 0.90 106.00
6 25 25 1.38 109.00
7 3 25 0.50 118.00
7 3 16 0.86 110.60
8 20 22 0.56 117.30
8 20 26 0.56 115.00
9 3 25 0.50 115.00
9 20 22 0.56 118.70
9 20 26 0.56 116.50
12 20 13 1.03 111.11
12 20 22 0.35 115.30
12 20 26 0.35 114.70
13 20 22 0.36 117.70
13 20 26 0.36 110.50
14 9 20 0.54 137.90
15 16 16 0.95 104.10
15 22 20 0.63 119.50
15 22 27 0.95 104.10
16 15 22 1.10 93.00
16 16 27 0.95 105.70
16 27 22 0.70 117.40
16 27 26 0.95 126.10
19 6 25 0.71 109.00
19 25 25 1.46 111.004 20 22 27 0.27 87.504 20 26 27 0.52 92.20
20 26 28 -0.02 136.804 22 20 26 0.30 85.204 22 27 26 0.35 93.40
27 26 28 1.59 130.60
2 25 0.05
3 16 0.80
3 25 0.80
9 20 0.05
20 26 0.80
26 27 0.80
APPENDIX 3
CEPARAN
125 19 6 68 18 78.5 1 3 16 16 0.34 11.10 0.00 1 3 16 32 0.00 0.00 -0.09 1 3 9 20 1.80 6.49 -6.23 1 6 2 2 3.53 2.30 -2.53 1 8 20 5 0.00 0.00 0.52 1 8 20 22-0.20 0.73 0.80 1 8 20 31 0.00 0.00 0.00 1 15 22 5 0.00 0.00 0.00 1 15 22 20 2.50 3.60 0.00 1 15 22 32 2.50 3.00 1.00 1 16 1 5 0.00 0.00 0.27 1 16 1 15 1.68 1.11 -0.20 1 16 1 32 0.00 0.00 0.00 1 16 15 22 -1.00 3.01 1.86 1 16 16 3 0.00 15.00 0.00 1 16 16 5 0.00 0.00 -0.90 1 16 16 15 -0.45 27.10 -0.78 1 16 16 32 0.00 15.00 0.00 1 20 9 3 0.00 0.00 0.06 1 20 22 5 0.0 0.0 2.0 1 20 22 27 0.00 0.00 0.10 1 20 26 27 0.0 0.00 -0.09 1 20 26 28 0.0 0.00 0.27 1 32 22 15 4.97 6.13 5.47 1 32 22 20 0.0 1.00 -0.56 1 32 22 5 0.0 0.0 0.0 1 32 31 20 -4.00 3.00 0.40 1 32 31 28 -1.00 3.00 2.00 2 1 3 9 0.00 -0.50 -1.70 2 2 1 3 0.00 0.00 0.50 2 6 1 3 0.00 0.00 -0.60 2 6 1 5 0.00 0.00 0.53 3 1 16 1 0.00 0.00 0.00 3 1 32 22 -1.00 -0.08 0.40 3 1 32 31 -1.00 -0.53 1.13 3 9 20 5 0.00 0.00 0.51 3 9 20 22 0.00 0.00 0.01 3 9 20 31 - 3.50 -0.05 -4.30 3 16 16 15 -1.75 0.30 1.50 3 16 32 22 -1.00 -0.80 0.40 3 16 32 31 -1.00 -0.53 1.13 5 1 3 16 0.00 0.00 0.00 5 1 3 30 0.00 0.00 -0.09 5 1 15 22 0.00 0.00 0.00 5 1 16 15 0.00 0.00 0.40 5 1 16 16 0.00 0.00 0.27 5 1 20 9 0.00 0.49 0.16 5 1 20 22 0.00 0.00 0.27 5 1 20 26 0.00 0.00 0.16
5 1 32 22 0.00 0.00 0.40 5 1 32 31 0.00 0.00 0.04 5 16 3 7 0.00 0.00 -0.04 5 16 3 29 0.00 0.00 -0.04 5 16 3 30 0.00 0.00 -0.09 5 16 15 22 0.00 0.00 -0.10 5 16 16 15 0.00 0.00 -0.80 5 16 32 22 0.00 0.00 0.40 5 16 32 31 0.00 0.00 0.04 5 20 9 14 0.00 0.00 0.00 5 20 22 5 0.00 0.00 1.30 5 20 22 15 0.00 0.00 0.04 5 20 22 32 0.00 0.00 0.10 5 20 31 32 0.00 0.00 -0.09 5 20 31 28 0.00 0.00 0.21 5 22 15 16 0.00 0.00 0.00 5 22 20 8 0.00 0.00 0.20 5 22 20 9 0.00 0.00 0.20 5 22 20 12 0.00 3.00 0.40 5 22. 20 13 0.00 5.00 0.20 5 22 20 31 0.00 0.00 0.87 5 22 32 16 0.00 0.00 0.00 5 22 32 31 0.00 0.00 0.98 6 1 3 7 0.00 0.00 -0.04 6 1 3 9 0.00 0.00 -0.04 7 3 9 20 0.00 7.19 0.00 7 3 16 16 0.00 0.00 -0.04 7 3 16 32 0.00 0.00 -0.04 8 20 22 32 0.00 0.00 0.40 8 20 31 32-4.30 5.00 -1.50 8 20 31 28-3.50 3.00 8.00 9 20 22 15 0.50 0.00 1.00 9 20 22 32 0.00 0.00 0.40 9 20 31 32-4.30 5.00 -1.50 9 20 31 28-3.50 3.00 8.0012 20 22 15 0.00 0.00 0.0412 20 22 32 0.00 0.00 0.5012 20 31 32 0.00 0.00 -0.0912 20 31 .28 COO 0.00 0.2113 20 22 15 0.50 2.75 3.0013 20 22 32 0.00 0.00 1.4013 20 31 32-4.30 5.00 -1.5013 20 31 28-1.50 5.00 8.0014 9 20 22 0.00 0.00 0.01 14 9 20 26 0.00 0.00 0.0114 9 20 31 0.00 0.00 0.0115 1 16 16 1.68 1.10 -0.33 15 16 16 32-0.75 2.00 -0.9015 22 20 31 0.00 1.00 1.0015 22 30 16-3.00 7.00 0.0015 22 32 31 0.00 1.00 0.3016 1 3 30 0.00 0.00 -0.3516 1 15 22 1.67 1.11 -0.1816 1 32 22-1.00 2.50 0.40
16 1 32 31-0.50 0.50 2.50
16 15 22 20- 2.50 3.60 -3.00
16 15 22 32- 2.50 3.00 -1.00
16 16 1 3 0 .00 0.00 0.90
16 16 1 32 0. 0. 0.
16 16 3 29 0.00 10.00 0.00
16 16 3 30 0.00 10.00 0.00
16 16 15 22 0.00 2.50 0.40
16 16 32 22 6.34 8.05 3.16
16 16 32 31- 3.34 6.00 0.00
16 32 22 20 0.00 1.00 -0.50
16 32 31 20- 4.00 3.00 0.40
16 32 31 28-1.00 3.00 2.004 20 22 32 31 1.50 10.00 1.004 20 31 32 22-1.00 8.50 5.00 4 22 20 31 32-1.00 9.00 3.00
22 20 31 28 0.20 3.50 -2.50
22 32 31 28 0.20 8.00 -4.704 31 20 22 32 -2 .65 6.10 0.20
32 16. 3 29 0 .00 0.00 -0.06
32 1 3 30 0 .00 0.00 -0.09
32 16 3 30 0 .00 0.00 -0.09
1 15 3.02 1.806
1 32 4.10 1.449
15 22 2.72 1.752
1 16 4.55 1.486
15 16 3.45 1.790
16 16 10.10 1.310
16 32 5.34 1.413
3 16 3.05 1.550
3 30 10.01 1.240
5 16 5.18 1.101
22 32 4.55 1.413
31 32 4.57 1.396
20 22 4.58 1.564
9 20 5.70 1.449
20 31 4.53 1.527
28 31 12.48 1.199
1 5 4.39 1.081
5 22 4.20 1.081
5 20 4.53 1.081
1 16 0.000
3 16 5.872
3 30 3.950
5 20 0.000
5 22 0.000
9 20 0.000
1 15 - 1.347
15 22 0.672
15 16 0.755
15 22 0.448
1 32 0.756
16 16 0.000
16 32 1.192
20 22 -0.343
20 31 -1.628
22 32 0.977
31 32 2.117
28 31 -1.659
16 0. 044 1.920
20 0. 044 1.920
30 0. 066 1.740
31 0. 044 1.920
32 0. 055 1.820
28 0. 066 1.740
1 3 16 0.40 115.00
1 3 30 0.64 116.50
1 6 2 0.77 110.80
1 8 20 0.63 110.00
1 15 22 0.76 96.00
1 16 1 0.74 113.90 1 1 16 1 0.45 111.20 2 1 16 1 0.45 112.40 3 1 16 . 5 0.36 109.40
1 16 15 0.22 109.80
1 16 16 1.05 122.00
1 32 22 0.97 127.00
1 32 31 0.95 136.70
3 1 6 0.70 106.00
3 1 32 0.83 108.40
3 9 20 0.53 121.20
3 16 5 0.45 107.90
3 16 16 0.59 113.90
3 16 32 0.83 111.30
5 1 16 0.36 109.40
5 1 5 0.39 110.60
5 1 15 0.44 108.30
5 1 16 0.46 106.00
5 1 32 0.36 110.00
5 16 15 0.47 112.00
5 16 16 0.47 113.36
5 16 32 0.58 100.00
5 20 8 0.36 98.90
5 20 9 0.54 98.90
5 20 22 0.50 115.10
5 20 31 0.38 112.20
5 22 15 0.36 107.90
5 22 20 0.49 114.10
5 22 32 0.55 118.00
7 3 16 0.86 110.60
8 20 22 0.56 117.30
8 20 31 0.56 115.00
9 20 22 0.74 118.70
9 20 31 0.73 116.50
12 20 13 1.03 111.11
12 20 22 0.35 115.30
12 20 31 0.35 114.70
13 20 22 0.36 117.70
13 20 31 0.36 110.50
14 9 20 0.53 137.90
15 1 16 1.09 117.00
15 16 16 1.07 131.10
15 22 20 0.39 116.00
15 22 32 0.62 111.00
16 1 3 0.67 112.70
16 1 32 1.04 110.60
16 3 30 1.17 116.50
16 15 22 1.04 97.60
16 16 32 1.16 120.00
16 32 22 0.97 126.10
16 32 31 0.41 134.004 20 22 32 1.17 88.304 20 31 32 0.94 90.30
20 31 28 0.69 138.004 22 20 31 1.24 85.804 22 32 31 1.01 94.60
30 3 30 0.85 126.00
32 31 28 0.67 132.00
3 16 0.80
3 30 0.80
9 20 0.05
20 31 0.80
31 32 0.80
APPENDIX 4
PROGRAMME FOR DOCKING OF TWO MOLECULES
PARAMETER (NT=150)
PARAMETER (NG=300)
CHARACTER*2 ASYM , TITLE
INTEGER TYPEA,TYPEB ,TYP
COMMON/COOD / COORD(3,NG), CHARGE (NG)
COMMON/TYPE / TYPEA(NT),TYPEB(NT), TYP(NG)
COMMON/SYMM / ASYM(NG), TITLE (40)
COMMON/PARAM/ VEP (NG) ,VRA(NG)
COMMON/CORD / XA(NT),YA(NT), ZA(NT) ,XB (NT) ,YB
COMMON/FINAL/ TXB (NT) , TYB (NT) , TZB (NT) , CA(NT)
COMMON/INFO / NA,NB, IP1, IP2, IP3, IP4, R1,R2, Cl
COMMON/PATH/MYWAY
DIMENSION X(5) ,E(5)
DATA E /5*0.01/
READ (8, 10 ) TITLE
10 FORMAT(40A2)
READ(8,*) IP1,IP2,IP3,IP4 ,MYWAY, Rl, R2, SC C MYWAY=1 : DISTANCE
C MYWAY=2 : ENERGY
C SC = SPECIAL CHARGE
CALL COMBIN(NA,NB)
READ(8,*) THETA,PI,XROT,YROT,ZROT , SCALE, JCO
E(l) = EE1
E(2) = EE1
E(3) = EE1
E(4) = EE1
E(5) = EE1
C READ(5,*) (E(I),I=1,5)
C SPECIAL CHARGE FOR IP2 AND IP4
CIP2= SC
CIP4= -SC
IPRINT=1
ICON = 1
C CONVERT DEGREE TO RADIAN
DEGREE=57.29577951D0
X(l)= THETA/DEGREE
X(2)= PI/DEGREE
X(3)= XROT/DEGREE
X(4)= YROT/DEGREE
X(5)= ZROT/DEGREE
NVAR=5
C C READ COORDINATE WITH MM FORMAT
READ(4,20) (XA(I),YA(I),ZA(I),TYPEA(I),I=1,N 20 FORMAT(2(3F10.5,I5,5X))
READ(5,20) (XB(I),YB(I),ZB(I),TYPEB(I),1=1,N CALL SYMBOL
CALL IWRITE
CALL PARM
CALL CHARG
WRITE(6,22) (CHARGE(I),I=1,12)
22 FORMAT(3X,6F10.4)
C
CALL OPTIM(X,NVAR, SCALE, IPRINT, ICON,E)
C C CONVERT RADIAN TO DEGREE
DO 30 J=1,5
30 X(J)= X(J)*DEGREE
WRITE (6, 35) X
35 FORMAT(4X,' OPTIMIZED THETA-PI-X-Y-Z ANGLES C WRITE BOND DISTANCE BETWEEN IP2 AND IP4
X1=XA(IP2)
Y1=YA(IP2)
Z1=ZA(IP2)
X2=TXB(IP4)
Y2=TYB(IP4)
Z2=TZB(IP4)
R12=DIST(X1,Y1,Z1,X2,Y2,Z2)
WRITE (6, 40) IP2 ,IP4 ,R12
DO 50 K=1,NA
COORD(1,K)=XA(K)
COORD(2,K)=YA(K)
COORD(3,K)=ZA(K)
50 CONTINUE
NTOT=NA+NB
DO 60 KK=1,NB
COORD( 1,NA+KK) =TXB (KK)
COORD(2,NA+KK) =TYB (KK)
COORD(3,NA+KK) =TZB (KK)
60 CONTINUE
40 FORMAT(//,' BOND LENGTH BETWEEN ',I3,' OF A 1,F10.5,' ANGSTROM',//)
CALL CHEMG(NTOT)
CALL MMDATA C WRITE FINAL CARTESIAN COORDINATE FOR CHEMGR
5 WRITE (6,' (//lOX, ' 'FINAL CARTESIAN COORDINA
WRITE(6,' (4X,''NO.'',7X,''ATOM'',9X,'*X'', 1 9X, ''Y'',9X,*'Z'',/)')
WRITE(6,' (I6,8X,A2,4X,3F10.5)')
1 (I,ASYM(I), (COORD(J,I),J=1,3),I=1,NTOT) C
STOP
END C ROUTINE FOR OUTPUT IF INITIAL COORDINATES
SUBROUTINE IWRITE
PARAMETER (NT=150)
PARAMETER (NG=300)
CHARACTER*2 ASYM ,TITLE
INTEGER TYPEA,TYPEB ,TYP
COMMON/COOD/ COORD(3,NG) ,CHARGE (NG)
COMMON/TYPE/TYPEA(NT) ,TYPEB(NT) ,TYP(NG)
COMMON/SYMM/ASYM(NG) ,TITLE (40)
COMMON/CORD/XA(NT) ,YA(NT) , ZA(NT) ,XB(NT) ,YB(N COMMON/FINAL/TXB(NT) ,TYB(NT) ,TZB(NT) ,CA(NT) , COMMON/INFO / NA,NB, IP1, IP2, IP3, IP4,R1,R2,CI WRITE (6, 15) TITLE
15 FORMAT(1H1, /////,
1 10X, ' *************************************
2 10x , ' COORDINATES OF SUPERMOLECULE
3 15X, 40A2 , /,
4 10X , ' *************************************
C WRITE CARTESIAN COORDINATE
WRITE (6, ' (//10X, ' 'INITIAL CARTESIAN COORDI
WRITE (6, ' (4X, ' 'NO. ' ' , 7X, ' 'ATOM' ' , 9X, ' 'X' ', 1 9X, ' 'Y' ',9X, ' 'Z' ',/)')
WRITE (6, ' (I6,8X,A2,4X,3F10.5)')
1 (I,ASYM(I),XA(I),YA(I),ZA(I),I=1,NA)
C
WRITE (6,' (////10X, ' 'INITIAL CARTESIAN COOR
WRITE(6, ' (4X, ' 'NO. ' ' , 7X, ' 'ATOM' ',9X, ' 'X'', 1 9X, ' 'Y' ',9X, ' 'Z' ',/)')
WRITE(6, ' (I6,8X,A2,4X,3F10.5)')
1 (I,ASYM(NA+I), XB(I),YB(I),ZB(I),I=1,NB)
WRITE (6, ' (///)')
RETURN
END
SUBROUTINE OPTIM (X,N,ESCALE, IPRINT, ICON,E)
PARAMETER (NT=150)
DIMENSION W( 1000) ,X(5) ,E (5)
MAXIT=100
DDMAG=0.1*ESCALE
SCER=0.05/ESCALE
JJ=N*N+N
JJJ=JJ+N
K=N+1
NFCC=1
IND=1
INN=1
DO 1 I=1,N
DO 2 J=1,N
W(K)=0.
IF(I-J)4,3,4
3 W(K)=ABS(E(I))
W(I)=ESCALE
4 K=K+1
2 CONTINUE
1 CONTINUE
ITERC=1
ISGRAD=2
CALL CALCFX(N,X,F,EW,ECO,EIDS)
FKEEP=ABS (F) +ABS (F)
5 ITONE=l
FP=F
SUM=0.
IXP=JJ
DO 6 I=1,N
IXP=IXP+1
W(IXP) =X(I)
6 CONTINUE
IDIRN=N+1
ILINE=1
7 DMAX=W(ILINE)
DACC=DMAX*SCER
DMAG=MIN (DDMAG,0.1*DMAX)
DMAG=MAX(DMAG, 20.*DACC)
DDMAX=10.*DMAG
GO TO (70,70,71),ITONE
70 DL=0.
D = DMAG
FPREV=F
IS=5
FA=F
DA=DL
8 DD=D-DL
DL=D
58 K=IDIRN
DO 9 1=1,N
X(I)=X(I)+DD*W(K)
K=K+1
9 CONTINUE
CALL CALCFX(N,X,F,EW,ECO,EDIS)
NFCC=NFCC+1
GO TO (10, 11, 12,13, 14, 96),IS
14 IF(F-FA)15,16,24
16 IF (ABS (D) -DMAX) 17,17,18
17 D=D+D
GO TO 8
18 WRITE (6, 19)
19 FORMAT(5X,44HVA04A MAXIMUM CHANGE DOES NOT A GO TO 500
15 FB=F
DB=D
GO TO 21
24 FB=FA
DB=DA
FA=F
DA=D
21 GO TO (83,23),ISGRAD
23 D=DB+DB-DA
IS=1
GO TO 8
83 D=0.5*(DA+DB-(FA-FB)/(DA-DB))
IS=4
IF((DA-D)*(D-DB))25,8,8
25 IS=1
IF (ABS (D-DB) -DDMAX) 8,8,26
26 D=DB+SIGN(DDMAX,DB-DA)
IS=1
DDMAX=DDMAX+DDMAX
DDMAG=DDMAG+DDMAG
IF (DDMAX-DMAX) 8,8,27
27 DDMAX=DMAX
GO TO 8
13 IF(F-FA)28,23,23
28 FC=FB
DC=DB
29 FB=F
DB=D
GO TO 30
12 IF(F-FB)28,28,31
31 FA=F
DA=D
GO TO 30
11 IF(F-FB)32,10,10
32 FA=FB
DA=DB
GO TO 29
71 DL=1.
DDMAX=5.
FA=FP
DA=-1.
FB=FHOLD
DB=0.
D=l.
10 FC=F
DC=D
30 A=(DB-DC)*(FA-FC)
B= (DC-DA) *(FB-FC)
IF( (A+B)* (DA-DC)) 33,33,34
33 FA=FB
DA=DB
FB=FC
DB=DC
GO TO 26
34 D=0.5* (A*(DB+DC)+B*(DA+DC))/(A+B) DI=DB
FI=FB
IF(FB-FC)44,44,43
43 DI=DC
FI=FC
44 GO TO (86,86,85),ITONE
85 ITONE=2
GO TO 45
86 IF (ABS(D-DI)-DACC) 41,41,93
93 IF (ABS(D-DI)-0.03*ABS(D)) 41,41,45 45 IF ( (DA-DC) * (DC-D) ) 47,46,46
46 FA=FB
DA=DB
FB=FC
DB=DC
GO TO 25
47 IS=2
IF ( (DB-D)*(D-DC)) 48,8,8
48 IS=3
GO TO 8
41 F=FI
D=DI-DL
DD=SQRT((DC-DB)*(DC-DA)*(DA-DB)/(A+B))
DO 49 1=1,N
X(I)=X(I)+D*W(IDIRN)
W(IDIRN) =DD*W(IDIRN)
IDIRN=IDIRN+1
49 CONTINUE
W(ILINE) =W(ILINE)/DD
ILINE=ILINE+1
IF(IPRINT-1)51,50,51
50 WRITE(6,52)ITERC,NFCC,F
WRITE (7, 52) ITERC,NFCC,F
52 FORMAT (3X, ' ITERATION' ,15,19,' FUNCTION VAL WRITE (6, 68) EW,ECO,EDIS
WRITE (7, 68) EW,ECO,EDIS
68 FORMAT (3X, 'REP. = ',F12.5,' ATT. =',F12.5, GO TO(51,53),IPRINT
51 GO TO (55,38),ITONE
55 IF (FPREV-F-SUM) 94,95,95
95 SUM=FPREV-F
JIL=ILINE
94 IF (IDIRN-JJ) 7,7,84
84 GO TO (92,72),IND
92 FHOLD=F
IS=6
IXP=JJ
DO 59 1=1,N
IXP=IXP+1
W(IXP)=X(I)-W(IXP)
59 CONTINUE
DD=1.
GO TO 58
96 GO TO (112,87),IND
112 IF (FP-F) 37,91,91
91 D=2. *(FP+F-2.*FHOLD)/(FP-F)**2
IF (D*(FP-FHOLD-SUM)**2-SUM) 87,37,37
87 J=JIL*N+1
IF (J-JJ) 60,60,61
60 DO 62 I=J,JJ
K=I-N
W(K)=W(I)
62 CONTINUE
DO 97 I=JIL,N
W(I-1)=W(I)
97 CONTINUE
61 IDIRN=IDIRN-N
ITONE=3
K=IDIRN
IXP=JJ
AAA=0.
DO 65 1=1,N
IXP=IXP+1
W(K)=W(IXP)
IF (AAA-ABS(W(K)/E(I))) 66,67,67
66 AAA=ABS(W(K)/E(I))
67 K=K+1
65 CONTINUE
DDMAG=1.
W(N)=ESCALE/AAA
ILINE=N
GO TO 7
37 IXP=JJ
AAA=0.
F=FHOLD
DO 99 I=1,N
IXP=IXP+1
X(I)=X(I)-W(IXP)
IF (AAA*ABS(E(I))-ABS(W(IXP))) 98,99,99 98 AAA=ABS(W(IXP)/E(I))
99 CONTINUE
GO TO 72
38 AAA=AAA*(1.+DI)
GO TO (72,106),IND
72 IF (IPRINT-2) 53,50,50
53 GO TO (109,88),IND
109 IF (AAA-0.1) 89,89,76
89 GO TO (20, 116), ICON
116 IND=2
GO TO (100, 101), INN
100 INN=2
K=JJJ
DO 102 I=1,N
K=K+1
W(K)=X(I)
X(I)=X(I)+10.*E(I)
102 CONTINUE
FKEEP=F
CALL CALCFX(N,X,F,EW,ECO,EDIS)
NFCC=NFCC+1
DDMAG=0.
GO TO 108
76 IF (F-FP) 35,78,78
78 WRITE (6, 80)
80 FORMAT (5X,37HVA04A ACCURACY LIMITED BY ERRO GO TO 500
88 IND=1
35 DDMAG=0.4*SQRT(FP-F)
IF(DDMAG.GE.1.0E60) DDMAG=1.0E60
ISGRAD=1
108 ITERC=ITERC+1
IF (ITERC-MAXIT) 5,5,81
81 WRITE(6,82)MAXIT
82 FORMAT(15, 30H ITERATIONS COMPLETED BY VA04A) IF (F-FKEEP) 500,500,110
110 F=FKEEP
DO 111 I=1,N
JJJ=JJJ+1
X(I)=W(JJJ)
111 CONTINUE
GO TO 20
101 JIL=1
FP=FKEEP
IF (F-FKEEP) 105,78,104
104 JIL=2
FP=F
F=FKEEP
105 IXP=JJ
DO 113 I=1,N
IXP=IXP+1
K=IXP+N
GO TO (114,115),JIL
114 W(IXP)=W(K)
GO TO 113
115 W(IXP)=X(I)
X(I)=W(K)
113 CONTINUE
JIL=2
GO TO 92
106 IF (AAA-0.1) 20,20,107
20 WRITE (6, 200)
WRITE(6,201)
WRITE (7, 201)
201 FORMAT(5X,' THE FUNCTION VALUE HAS BEEN MIN
WRITE (6, 200)
200 FORMAT(/1X, '******************************** 500 RETURN
107 INN=1
GO TO 35
ENDC
SUBROUTINE PARM
PARAMETER (NT=150)
PARAMETER (NG=300)
CHARACTER*2 ASYM ,TITLE
INTEGER TYPEA,TYPEB ,TYP
COMMON/PARAM/ VEP(NG) ,VRA(NG)
COMMON/INFO / NA,NB,IP1,IP2,IP3,IP4,R1,R2,CI
COMMON/TYPE / TYPEA(NT),TYPEB(NT),TYP(NG)
DIMENSION VEPS (60),VRAD(60)
C
DATA VRAD/
1 1.900, 1.940, 1.940, 1.940, 1.500, 1.740, 1
2 -1.0 , 1.780, 1.740, 1.900, 0.930, 2.110, 1
3 1.820, 1.920, 1.200, 1.920, 1.325, 0.900, 1
4 1.740, 1.90 , 1.780 , 1.92, 1.82, -1.0 , -1.0
5 -1.0 , -1.0 , -1.0 , -1.0 , -1.0 , -1.0 , 1 DATA VEPS/
1 0.044, 0.044, 0.044, 0.044, 0.047, 0.050, 0
2 -1.0 , 0.066, 0.050, 0.030, 0.017, 0.202, 0
3 0.055, 0.044, 0.036, 0.044, 0.034, 0.015, 0
4 0.066, 0.044, 0.066, 0.044, 0.055,-1.0 , -1.
5 -1.0 , -1.0 , -1.0 , -1.0 , -1.0 , -1.0 , IF(JCON.GT.O) THEN
DO 10 J=1,JCON
READ(5,*) ITYPE, EPS, RAD
VEPS(ITYPE) = EPS
VRAD(ITYPE) = RAD
10 CONTINUE
ENDIF
DO 20 1=1,NA
VEP(I) = VEPS(TYPEA(I))
IF(VEP(I).LE.0.0) THEN
WRITE (7, 25) TYPEA(I)
ENDIF
VRA(I) = VRAD(TYPEA(I))
IF(VRA(I).LE.0.0) THEN
WRITE (7, 25) TYPEA(I)
25 FORMAT(4X,' CHECK YOUR VAN DER WAAL DATA
ENDIF
20 CONTINUE
C
DO 30 I=1,NB
VEP(NA+I) = VEPS(TYPEB(I))
IF(VEP(NA+I).LE.0.0) THEN
WRITE (7, 25) TYPEB(I)
ENDIF
VRA(NA+I) = VRAD(TYPEB(I))
IF(VRA(NA+I).LE.0.0) THEN
WRITE (7, 25) TYPEB(I)
ENDIF
30 CONTINUE
RETURN
END
SUBROUTINE ENERGY(ETOT,EV,ETOTl,EDIS)
C FUNCTION PROGRAM FOR SUPER-MOLECULE
PARAMETER (NT=150)
PARAMETER (NG=300)
CHARACTER*2 ASYM , TITLE
INTEGER TYPEA,TYPEB , TYP
COMMON/COOD/ COORD(3,NG) , CHARGE (NG) Λ
COMMON/TYPE/TYPEA(NT), TYPEB (NT) , TYP (NG)
COMMON/CORD/XA(NT), YA(NT) ,ZA(NT) ,XB(NT) ,YB(N
COMMON/FINAL/TXB (NT), TYB (NT) , TZB (NT) , CA(NT) ,
COMMON/PARAM/ VEP(NG) ,VRA(NG)
COMMON/INFO / NA,NB, IP1,IP2,IP3,IP4,R1,R2,CI
COMMON/PATH/MYWAY
C CALCULATION OF VAN DER WALLS ENERGY(ONLY 1-5
DIELC=78.5
C GO TO (1 ,2), MYWAY
X1=XA(IP2)
Y1=YA(IP2)
Z1=ZA(IP2)
X2=TXB(IP4)
Y2=TYB(IP4)
Z2=TZB(IP4)
ETOT1=DIST(X1,Y1,Z1,X2,Y2,Z2)
ETOT1= ABS(ETOT1-R2) *500.0
IF(MYWAY.EQ.1) THEN
ETOT=ET0T1
RETURN ENDIF
2 EV=0.0
EC=0.0
DO 500 I=1,NA
XI=XA(I)
YI=YA(I)
ZI=ZA(I)
DO 500 K=1,NB
XK=TXB(K)
YK=TYB(K)
ZK=TZB (K)
RIK=DIST(XI,YI,ZI,XK,YK,ZK)
ECOUL=332.0*CHARGE (I) *CHARGE (NA+K) / (DIELC*RI
VEPI=VEP(I)
VEPK=VEP (NA+K)
VRAI=VRA(I)
VRAK=VRA(NA+K)
EPS=SQRT(VEPI*VEPK)
RV=VRAI+VRAK
P=RV/RIK
IF(P.GT.3.31) GO TO 30
IF (P.LT.0.072) THEN
E=EPS*(-2.25*P**6)
GO TO 35
ENDIF
E=EPS* (290000.0*EXP ( -12.5/P) -2.25*P**6)
GO TO 40
30 E=EPS*336.176*P*P
35 CONTINUE
40 EV = EV+E
EC = EC +ECOUL
500 CONTINUE
ETOT=EV + ETOT1 + EC
C ETOT=EV + ETOT1
X1=XA(IP2)
Y1=YA(IP2)
Z1=ZA(IP2)
X2=TXB(IP4)
Y2=TYB(IP4)
Z2=TZB(IP4)
EDIS=DIST (X1 , Y1 , Z 1 , X2 , Y2 , Z2 )
RETURN
END C FUNCTION DIST
FUNCTION DIST (X1 , Y1 , Z 1 , X2 , Y2 , Z2 )
X=X1 -X2
Y=Y1-Y2
Z=Z1-Z2
DIST=SQRT (X*X+Y*Y+Z*Z)
RETURN
END
SUBROUTINE CALCFX(NVAR, X, ETOT, EV, EC, EDIS)
PARAMETER (NT=150)
PARAMETER (NG=300)
COMMON/CORD/XA(NT), YA(NT), ZA(NT), XB(NT), YB(N
COMMON/FINAL/TXB (NT), TYB (NT), TZB (NT), CA(NT),
COMMON/INFO / NA,NB, IP1, IP2, IP3, IP4, R1, R2 CI
DIMENSION X(5),TX(150), TY ( 150), TZ ( 150),XROT(
DIMENSION CTX(150), CTY(150), CTZ(150)
C CONVERSION OF POLAR COORDINATE TO CARTECIAN COOR
DX=R1*SIN(X(1))*COS(X(2))
DY=R1*SIN(X(1))*SIN(X(2))
DX=R1*COS(X(1))
C FIXING OF PROBE 2 APART FROM PROBE 1 BY R1 ANG.
PX=XA(IP1)+DX
PY=YA(IP1)+DY
PZ=ZA(IP1)+DZ
C CALCULATE DISTANCE VECTORS BETWEEN PROBE P(PX,P
DVX=PX-XB(IP3)
DVY=PY-YB(IP3)
DVZ=PZ-ZB(IP3)
C PARALLEL MOVEMENT OF B MOLECULE BY (DVX,DVY,DVZ
DO 10 IM=1,NB
TX(IM) = XB(IM) + DVX
TY(IM) = YB(IM) + DVY
TZ(IM) = ZB(IM) + DVZ
10 CONTINUE
C MOVE TO MAKE AN ORIGIN OF PROBE3(IP3) IN
DO 20 10=1,NB
IF(IO.EQ.IP3) GO TO 20
TX(IO)=TX(IO)-TX(IP3)
TY(IO)=TY(IO)-TY(IP3)
TZ(IO)=TZ(IO)-TZ(IP3)
20 CONTINUE
TX(IP3) = 0.0D0
TY(IP3) = 0.0D0
TZ(IP3) = 0.0D0
C ROTATION
CSX= COS(X(3))
SSX= SIN(X(3))
CSY= COS(X(4))
SSY= SIN(X(4))
CSZ= COS(X(5))
SSZ= SIN(X(5))
C X ROTATION
DO 30 I=1,9
30 XROT(I) = 0.0
XROT(l) = 1.0
XROT(5) = CSX
XROT(6) =-SSX
XROT(8) = SSX
XROT(9) = CSX
DO 40 1=1,9
40 YROT(I) = 0.0
YROT(1) = CSY
YROT(3) = SSY
YROT(5)= 1.0
YROT(7)= -SSY
YROT(9) = CSY
DO 50 1=1,9
50 ZROT(I)= 0.0
ZROT(1) = CSZ
ZROT(2) = SSZ
ZROT(4) =-SSZ
ZROT(5) = CSZ
ZROT(9) = 1.0
DO 60 J=1,NB
COXX = XROT(l)*TX (J ) +XROT(2)* TY(J ) +X COXY = XROT(4)*TX (J ) +XROT(5)* TY(J ) +X COXZ = XROT(7)*TX (J ) +XROT(8)* TY(J ) +X COYX. = YROT(1)*COXX +YROT(2)*COXY +YROT(3)*C COYY = YROT(4)*COXX +YROT(5)*COXY +YROT(6)*C COYZ = YROT(7)*COXX +YROT(8)*COXY +YROT(9)*C CTX(J) =ZROT(1)*COYX +ZROT(2)*COYY +ZROT(3)*C CTY(J)=ZROT(4)*COYX +ZROT(5)*COYY +ZROT(6)*C CTZ (J) =ZROT(7)*COYX +ZROT(8)*COYY +ZROT(9)*C
60 CONTINUE
C RETURN TO POINT P
DO 70 1= 1,NB
TXB(I) = CTX(I) + PX
TYB(I) = CTY(I) + PY
TZB(I) = CTZ (I) + PZ
70 CONTINUE
C
CALL ENERGY(ETOT,EV,EC,EDIS)
RETURN
END
SUBROUTINE COUL (ETOT,ER,EA)
PARAMETER (NT=150)
PARAMETER (NG=300)
CHARACTER*2 ASYM ,TITLE
COMMON/CORD/XA(NT) ,YA(NT) , ZA(NT) ,XB(NT) ,YB(N
COMMON/FINAL/TXB (NT) ,TYB (NT) ,TZB (NT) ,CA(NT) ,
COMMON/INFO / NA,NB,IP1,IP2,IP3,IP4,R1,R2,CI
ER=0.0
DO 10 I=1 , NA
X1=XA(I)
Y1=YA(I)
Z1=ZA(I)
DO 20 J=1,NB
X2=TXB(I)
Y2=TYB(I)
Z2=TZB(I)
ER =ER +(CA(I)*CB(J))/DIST(X1,Y1,Z1,X2,Y2,Z2
20 CONTINUE
10 CONTINUE
EA =0.0
X1=XA(IP2)
Y1=YA(IP2)
Z1=ZA(IP2)
X2=TXB(IP4)
Y2=TYB(IP4)
Z2=TZB(IP4)
EA =EA +(CIP2*CIP4)/DIST(X1,Y1,Z1,X2,Y2,Z2)
ETOT=ER + EA
RETURN
END C SUBPROGRAM TO GENERATE ATOM TYPE AND NET ATO SUBROUTINE CHARG PARAMETER (NG=300)
PARAMETER (NT=150)
INTEGER TYPEA,TYPEB , TYP
COMMON/COOD / COORD (3 ,NG) , CHARGE (NG)
COMMON/TYPE / TYPEA(NT),TYPEB(NT), TYP(NG) COMMON/INFO / NA,NB, IPl, IP2, IP3, IP4, R1,R2,CI DIMENSION DCHB(35)
DATA DCHB/ 0.241, 0.0 , 0.515, 0.0 , 0.0
1 -0.267, -0.509, 0.0 , -0.692 -0 .5
2 -0.135, 0.0 , 0.0 , 0.0 -0 . 6
3 0.0 , 0.243, 0.15 , 0.131 -0. 5
4 0.0 , -0.622, 0.515, 0.0 0 .0 DO 20 I=1,NA
CHARGE (I) =DCHB(TYPEA(I))
20 CONTINUE
C SPECIAL SIDE CHAIN FOR CARBONE C CHARGES FOR HYDANTON
DO 30 I=1,NB
CHARGE (NA+I) =DCHB (TYPEB (I))
30 CONTINUE
C CHARGE (NA+1) = -0.36
C CHARGE (NA+2) = 0.44
C CHARGE (NA+3) = -0.41
C CHARGE (NA+4) = 0.58
C CHARGE (NA+5) = -0.31
C CHARGE (NA+6) = 0.03
C CHARGE (NA+7) = -0.41
C CHARGE (NA+20)= 0.19
C CHARGE (NA+21) = 0.20
40 CHARGE (IP2)= CIP2
CHARGE (NA+IP4) = CIP4
WRITE (6, 22) (CHARGE (I), I=1, 12)
22 FORMAT(3X,6F10.4)
RETURN
END C
SUBROUTINE SYMBOL
PARAMETER (NT=150)
PARAMETER (NG=300)
CHARACTER*2 ASYM , TITLE
INTEGER TYPEA,TYPEB, TYP, HH,NN,OO, CC
COMMON/COOD/ COORD(3,NG) , CHARGE (NG)
COMMON/TYPE/TYPEA(NT) , TYPEB (NT) ,TYP (NG)
COMMON/SYMM/ASYM(NG) , TITLE (40)
COMMON/INFO / NA,NB, IP1, IP2,IP3,IP4,R1,R2,CI
DIMENSION HH(6),NN(7),00(6),CC(10)
DATA HH/5,14,23,21,24,25/
DATA NN/8,9,13,19,26,32,28/
DATA 00/6,7,11,12,28,30/
DATA CC/1,2,3,4,16,20,22,27,29,31/
NTOT=NA+NB
DO 1 I=1,NA
TYP(I)=TYPEA(I)
1 CONTINUE
DO 2 I=1,NB
TYP (NA+I) =TYPEB (I)
2 CONTINUE
1=0
10 CONTINUE
I=I+1
IF(I.GT.NTOT) GO TO 9
DO 20 K1=1,6
IF (TYP(I).EQ.HH(K1)) THEN
ASYM(I)=' H'
GO TO 10
ENDIF
20 CONTINUE
DO 301l=1,7
IF (TYP(I).EQ.NN(Kl)) THEN
ASYM(I)=' N'
GO TO 10
ENDIF
30 CONTINUE
DO 40 K1=1,6
IF(TYP(I).EQ.OO(Kl)) THEN
ASYM(I)=' 0'
GO TO 10
ENDIF
40 CONTINUE
DO 50 K1=1,10
IF(TYP(I).EQ.CC(K1)) THEN
ASYM(I)=' C'
GO TO 10
ENDIF
50 CONTINUE
IF (TYP(I).EQ.15) THEN
ASYM(I)= ' S'
GO TO 10
ELSE
WRITE (6, 100) TYP (I) , I
100 FORMAT(3X,' UNDEFINED ATOM TYPE. : ',13,' O
ENDIF
9 CONTINUE
RETURN END SUBROUTINE CHEMG(NTOT)
C
CHARACTER NAME1*2, NAME2*3 ,CTEMP*80 ,TEMP*
PARAMETER (NG=300)
PARAMETER (NT=150)
INTEGER IH, IN, IC, IO, IS, HH,NN, CC,OO, SS
COMMON/COOD/ COORD(3,NG), CHARGE (NG)
COMMON/SYMM/ASYM(NG), TITLE (40)
C
J=0
IONE=1
WRITE (10,1) NTOT,IONE,IONE
1 FORMAT(//,I3,I5,/,I6)
DO 33 I = l,NTOT
C READ(4,' (1X,3F10.4,5X,A1)' ,END=999) X,Y,Z,NA
X=COORD(1,I)
Y=COORD(2,I)
Z=COORD(3,I)
NAME1=ASYM(I)
IF( NAME1.EQ.' F') GO TO 33
J=J+1
IF (NAME1.EQ. ' H') THEN
IH = IH + 1
WRITE (NAME2,' (13)') IH
ELSEIF (NAME1.EQ.' N') THEN
IN = IN + 1
WRITE (NAME2,' (13)') IN
ELSEIF (NAME1.EQ.' C) THEN
IC = IC + 1
WRITE (NAME2,' (13)') IC
ELSEIF (NAME1.EQ. ' 0') THEN
10 = 10 + 1
WRITE (NAME2,'(13)') 10
ELSEIF (NAME1.EQ.' S') THEN
IS = IS + 1
WRITE (NAME2, ' (13)') IS
ELSE
WRITE (6, ' (' 'You have a problem on line' ',14, &')I
ENDIF
IF (NAME2(1:1).EQ.' ') THEN
NAME2(1:1) = NAME2(2:2)
NAME2(2:2) = NAME2 (3 : 3 )
NAME2 (3 : 3 ) = ' '
IF (NAME2(1:1).EQ.' ') THEN
NAME2(1:1) = NAME2(2:2)
NAME2(2:2) = ' '
ENDIF ENDIF WRITE(10,' (I4,A2,A3,1X,3F10.4)') J,NAME1,NAM
33 CONTINUE
C ENDIF RETURN END SUBROUTINE WRIT(X,Y,Z)
DIMENSION X(150),Y(150),Z(150) DO 5 1=1,6
5 WRITE(6,10) X(I),Y(I),Z(I)
10 FORMAT(4X,3F12.5)
RETURN END C
SUBROUTINE COMBIN (NA,NB)
DIMENSION ICON(16),IAT1(150),IAT2(150) CHARACTER*2 TT(30)
READ (4, 10) NA
10 FORMAT (62X, I3)
READ (5, 10) NB
NTOT=NA+NB
IONE=1
IFOUR =4
TIME=100.0
WRITE (16,20) NTOT,IFOUR,IONE,TIME 20 FORMAT(60X,I5,I2,3X,I5,F5.0)
READ(4,30) NCONA,NATA,NSPA
30 FORMAT(I5,20X,I5,15X,I5)
READ(5,30) NCONB,NATB,NSPB
NCOT=NCONA+NCONB
NATT=NATA+NATB
NSPT=NSPA+NSPB
WRITE (16, 30) NCOT,NATT,NSPT
IF(NSPA.NE.O) THEN
DO 50 I=1,NSPA
READ(4,40) TT
40 FORMAT(30A2)
WRITE (16,40) TT
50 CONTINUE
ENDIF
IF(NSPB.NE.0) THEN
DO 60 I=1,NSPB
READ (5, 40) TT
WRITE (16, 40) TT
60 CONTINUE
ENDIF
DO 70 IA=1,NCONA
READ(4,75) (ICON(I),I=1,16)
75 FORMAT(1615)
DO 80 IZ=1 , 16
ISZ=16
IF( ICON(IZ).EQ.0) THEN
ISZ=IZ -1
GO TO 85
ENDIF
80 CONTINUE
85 WRITE(16,75) (ICON(I), I=1, ISZ)
70 CONTINUE
DO 90 IB=1,NCONB
READ(5,75) (ICON(I), I=1, 16)
DO 100 IZ=1,16
ISZ=16
IF( ICON(IZ).EQ.0) THEN
ISZ=IZ -1
GO TO 95
ENDIF
100 CONTINUE
95 DO 110 I=1, ISZ
110 ICON(I)= ICON(I)+NA
WRITE(16,75) (ICON(I), I=1, ISZ)
90 CONTINUE
READ(4,75) (IAT1(I), IAT2 (I), I=1,NATA) NATA1=NATA+1
READ(5,75) (IAT1(I), IAT2 (I), I=NATA1,NATT) DO 120 IL=NATA1,NATT
IATl(IL) = IAT1(IL)+NA
IAT2(IL) = IAT2(IL)+NA
120 CONTINUE
WRITE(16,75) (IAT1 (I), IAT2 (I), I=1,NATT) RETURN END C SUBROUTINE FOR MM INPUT SUBROUTINE MMDATA PARAMETER (NT=150)
PARAMETER (NG=300)
CHARACTER*2 ASYM ,TITLE
INTEGER TYPEA, TYPEB ,TYP
COMMON/COOD / COORD(3,NG), CHARGE (NG)
COMMON/TYPE / TYPEA(NT), TYPEB (NT), TYP (NG) COMMON/SYMM / ASYM(NG), TITLE (40)
COMMON/PARAM/ VEP(NG) ,VRA(NG)
COMMON/CORD / XA(NT),YA(NT), ZA(NT),XB(NT),YB COMMON/FINAL/ TXB (NT) ,TYB (NT) ,TZB(NT), CA(NT) COMMON/INFO / NA,NB,IPl,IP2,IP3,IP4,R1,R2,CI NTOT=NA+NB
WRITE (16,20) (COORD(1,I), COORD(2,I), COORD(3, 20 FORMAT(2(3F10.5,I5,5X))
RETURN END