WO2005029049A1

WO2005029049A1 - Method for seeking dominating conformation of optically active molecule

Info

Publication number: WO2005029049A1
Application number: PCT/JP2004/005107
Authority: WO
Inventors: Hiroshi Izumi; Soko Yamagami; Shigeru Futamura
Original assignee: National Institute Of Advanced Industrial Science And Technology
Priority date: 2003-09-17
Filing date: 2004-04-09
Publication date: 2005-03-31
Also published as: JP3991106B2; JP2005091164A

Abstract

A method for seeking a dominating conformation of an optically active molecule in which the correlation between a labeled isomer conformation structure and its energy value in consideration of the stereoisomerism of a simplified model molecule of the optically active molecule is statistically analyzed, an appearance pattern of a stable conformation structure is extracted, and a dominating conformation of the optically active molecule is sought referring to the appearance pattern. This seeking method can be applied to optically active molecules having a large molecular weight such as organic molecules and capable of having a huge number of isomer conformation structures. The time and labor required to seek isomer conformation structures used for initial structures can be decreased to an irreducible minimum limit. Thus, a desired dominating conformation of an optically active molecule can be simply and easily sought in a short time.

Description

Description Method for searching for superior conformation of optically active molecule

The present invention relates to a method for simply and easily searching for a superior conformation of an optically active molecule. "King skill cup end

Both endocrine disruptors and drugs act by acting on receptors in the living body, and the evaluation of their functions requires enormous time and cost. Therefore, it has become an issue how to efficiently select candidate molecules, and drug discovery by pharmacological proteomics utilizing the whole-protein protein three-dimensional structure library and drug three-dimensional structure library is being performed. The foundation is the three-dimensional structure analysis, and the methods of X-ray crystallography and Awake R have been mainly used.

However, the X-ray crystallography has the restriction that a solid to be a crystal is required, and the employment R analysis is accurate in general systems except for special cases such as those that show nuclear Overhauser effect. The conformation information could not be obtained.

On the other hand, it is often the case that the drug does not show any medicinal effect even if only a small part of the structure of the drug is substituted.Therefore, it is necessary for proteomic drug discovery to obtain conformational information considering the degree of freedom of the substituent. I have.

In order to solve these problems, the present inventors have first set the infrared circular dichroism (VCD) band of chiral substances such as biomolecules to be extremely conformable. Have already proposed a new structural analysis method that utilizes VCD spectroscopy (Patent Document 1).

However, the present invention has the advantage that the use of VCD spectroscopy makes it possible to easily and easily determine the superior conformation of a compound having an asymmetric alkyl chain and the evenness of the number of carbon atoms in the alkyl chain with a sample having a very small number. However, according to the subsequent studies by the present inventors, the VCD band is very complicated in this structural analysis. Therefore, it is necessary to use theoretical calculations such as density functional theory together.In this case, in consideration of the initial structure of the molecule, it is necessary to search for rotamers derived from the rotation of covalent bonds between atoms. It turned out that there was a problem of being forced. That is, as a method for searching for rotamers and the like, a conformation creation program based on molecular force field calculation is often used (Non-Patent Document 1), but the stability of the conformation of the created rotamers and the like is considered. Since there is a large gap between the predicted energy value and the actual value of, almost all conformations must be considered as initial structures when using this conformation creation program. Instead, this has the new problem of having the potential to have a significant impact on the application to higher molecular weight molecules.

Therefore, in the above-mentioned conformational analysis method utilizing VCD spectroscopy, it is indispensable to search for rotamers and the like to be used for the initial structure. The conformation creation methods used up to now have to consider almost all created conformations as initial values, which requires a lot of time and limits the applicable molecular weight. There has been a need for a new conformational search method that can be applied to optically active molecules with large molecular weights such as biomolecules.

[Patent Document 1] Japanese Patent Application No. 200-3

[Non-Patent Document 1] H. Goto et al., /. AM. Chem. Soc., 1989, 111, 8950 Disclosure of the Invention

INDUSTRIAL APPLICABILITY The present invention overcomes the above problems, and can be applied to optically active molecules having a large molecular weight, such as biomolecules, which can have a huge number of isomeric conformations, and to be used for the initial structure. It is an object of the present invention to provide a method that can minimize the search for the rotamer, etc. of a compound to the minimum necessary, and can easily, easily, and easily search for the desired conformation of the desired optically active molecule in a short time. .

The present inventors have conducted intensive studies to solve the above problems, and as a result, created a simplified model molecule of an optically active molecule, firstly performed a conformational analysis on the abbreviated structure, and obtained the obtained rotation. By statistically analyzing the correlation between each conformational structure indexed from the stereoisomeric relationship including isomerism and its energy value, the appearance pattern of a stable conformational structure of the model molecule can be extracted. By using the The present inventors have found that a superior conformation of an optically active molecule can be searched for, and have completed the present invention.

That is, according to the present invention, the following inventions are provided.

(1) In the method of searching for the predominant conformation of an optically active molecule, the isomer conformational structure and its energy value previously indexed from the individual stereoisomers of the simplified model molecule of the optically active molecule Statistical analysis of the correlation between the two, extracting the appearance pattern of a stable conformational structure, and searching for the superior conformation of the optically active molecule based on the appearance pattern.

(2) Analyze the infrared circular dichroism spectrum using the appearance pattern of the isomer conformational structure indexed from the individual stereoisomers of the simplified model molecule of the optically active molecule. The method for searching for a superior conformation of an optically active molecule according to the above (1). Brief Description of Drawings

FIG. 1 is a typical flowchart of a method for searching for a superior conformation according to the present invention, and FIG. 2 is a diagram showing measured and predicted VCD spectra of an asymmetric alcohol compound (I) (n is 4). Fig. 3 shows the indexing of the conformational structure of the asymmetric alcohol compound (I) with isomers. Fig. 4 shows the measured and predicted VCD spectra of the asymmetric alcohol compound (I) (n: 5). Figure 5 shows the measured and predicted VCD spectra of permethrin compound (II). BEST MODE FOR CARRYING OUT THE INVENTION

The method of searching for the predominant conformation of an optically active molecule according to the present invention is based on the method of obtaining the conformational information of an optically active molecule such as an asymmetric alkyl alcohol compound or a c-permethrin compound, which can take an enormous number of conformations. Instead of using a theoretical calculation and data on all rotamers, etc., in order to retrieve them, a simplified model molecule of an optically active molecule was created instead of a method in which all isomer conformational structures were successively used. The conformational analysis was performed on the simplified model molecule having the abbreviated structure, and the correlation between the individual conformational structures indexed from the obtained stereoisomerism including rotational isomerism and their energy values. Of the conformational structure of the model molecule by statistical analysis In this method, the predominant conformation of the target optically active molecule is predicted and analyzed using this appearance pattern.

Therefore, the search method according to the present invention can be used as a means of conformational analysis of a compound such as a biological substance or an insecticide having an enormous number of conformations. It is expected to be fully utilized in applications such as the evaluation of the effects of harmful substances on the human body and drug discovery by pharmacological proteomics.

In the present invention, the optically active molecule to be searched may be any organic compound having optical activity and having a chain structure or a cyclic structure in a part of the structure. The organic compound having optical activity may be partially substituted with a functional group such as a hydroxyl group, a phenyl group, an alkene or a halogen.

As such optically active molecules, for example, the following compounds can be exemplified.

(-(+)-5_Methyl-1_heptanol, (-(+)-6-Methyl-1 -heptanol, Methyl_1_heptanol, (-(_)-6-Methyl-1-octanol, (-(+)-2-heptanol, (5)-(+)-2-octanol, (-(+)-2-nonanol,

2-decanol, 0?) _ (-)-2-heptanol, (-(-)-2-octanol, (R)-(-)-2-nonanol, (R)-(-) _ 2 -decanol , (1 & 3-(+)-c-permethrin, (3-(-)-c-permethrin, (3-(+)-c / '5-3_ (2,2-dichlorovinyl) -2,2) -Benzyl dimethylcyclopropanecarboxylate, (IR, 37?)-(-)-C / 5-3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylate The simplified model molecule of the optically active molecule referred to in the invention is a model with an abbreviated structure in which the optically active molecule is divided into basic structural units, and basic structural units having only the required characteristics are selected and assembled. Means a molecule.

Examples of the optically active molecule and its simplified model molecule include, for example, the following combinations.

(-(+)-5-Methyl_1-hepnool → (_ (+)-3-Methyl-1-pentanol, (-(+) _ 6-Methyl-1-octanol- (-(+ ) -3-Methyl-1-pentanol,)-(_) _ 5_methyl-1-hepanol → (-(-)-3-methyl-1-pentanol, (-(-)- 6-Methyl -Northanol → 0?)-(-)-3_Methyl-1_Penthanol, (S)-(+)-2-Heptanol → (S)-(+) -2 -Bennoru, (-(!) -2 -Taktanoru → (-(+)-2 -Penanol, (S)-(+)-2-nonanol → (5)-(+)-2-pentanol, (-(+)-2-decanol → (-(+)-2- Pentanol, (-(-)-2-Heptanol → (R) ― (-)-2-Pinanol, me-(-)-2-octanol → (R)-(-) -2- Ben-no-noru, (-)-2-nonanol— (-pentanol, (-(-)-2-decanol →

(One (one) —2—Pentanol, (1 & 3 — (+)-'5-permethrin → (1 & 3 ¹ )-(+) -c / 5-3- (2 , 2-Dimethyl mouth mouth propane power propane potency Benzyl ester of sulfonate,--Permethrin → 3-phenoxybenzyl alcohol, (IR, 3--(-) -c -Permetrie → ( \ R,?> R)-{-)-cis--(l, 2-dichroic biel) -2,2-dimethylcyclopropanecarboxylic acid benzyl ester, (\ R, 2R)-(-) -cis ~ Permethrin → 3-phenoxybenzyl alcohol, (1 & 3-(+) / 5-3- (2,2-dic-mouth vinyl) -2,2-dimethylcyclopropane benzyl ester of sulfonic acid— ( 1 & 3-(+)-3- (2,2-Dimethyl vinyl) -2,2_dimethylcyclopropanecarboxylic acid methyl ester, (IJi, (-) -cis-^-(2,2-dichloro) Vinyl) -2,2-dimethylcyclopropanecarboxylic acid benzyl ester → (1 A 3-(-) -cis-3- (2 2-dichlorovinyl) - 2, 2-dimethyl-cyclopropane force Lupo phosphate methyl esters.

In the present invention, the correlation between the isomer conformational structure indexed from the individual stereoisomers of the simplified model molecule and its energy value is statistically analyzed, and the appearance pattern of a stable conformational structure is extracted. Search for the superior conformation of the optically active molecule based on the appearance pattern.

In the analysis of the correlation between the individual conformational structure of the simplified model molecule and its energy value in the present invention, for each part having a stereoisomeric relationship such as rotational isomerism in order to facilitate the analysis of the correlation. It is desirable to attach a tag with the numbers and symbols defined in, and to index the conformational structure. Specifically, in order to understand the conformational structure of isomers indexed from individual stereoisomers of the simplified model molecule, for example, in the case of stereoisomers derived from bond rotation, the trans Assign a number such as 2 to the clockwise Gauche conformation and 3 to the counterclockwise Gauche conformation, and if necessary, add a symbol indicating the position of the bond to give each isomer. Conformations may be distinguished.

There is no particular limitation on the calculation method for the energy value of the indexed conformational structure, but energy calculation by the density functional method using B3LYP functional is preferably used. Furthermore, in order to statistically analyze the correlation between the indexed isomer conformational structure and its energy value and extract the appearance pattern of a stable conformational structure, the energy value obtained by theoretical calculation must be stable. It is desirable to arrange the isomeric conformational structures in a suitable order and to statistically analyze the tags used for the indexing to extract a common appearance pattern found in the stable isomeric conformational structure. To search for the predominant conformation of the optically active molecule based on the extracted appearance pattern, only the appearance pattern extracted from the simplified model molecule is applied to the optically active molecule, and the isomer stereo conformation structure is obtained. May be narrowed down.

There is no particular limitation on the method of verifying the searched superior conformation, but preferably, the infrared circle dichroism band measured from the actually measured infrared circular dichroism band of the optically active molecule and the infrared circular dichroism predicted from the isomer conformational structure. A homology comparison with the chromatic band is used.

The approximation method used for fitting the infrared circular dichroic band is not particularly limited, but preferably a mouth-Lentz function approximation or a Gaussian function approximation is used. The method of predicting the infrared circular dichroic band is not particularly limited, but preferably the frequency calculation by the density functional method using B3LYP functional is used. For the isomer conformational structure used for the prediction of the infrared circular dichroic band, only the superior conformation derived by the above-mentioned search method is selected from a huge number of conformations, Just fine. There is no particular limitation on the integration time of the infrared circular dichroism measurement, but 20 minutes to 4 hours are desirable to obtain sufficient S / N.

As the solvent used for the infrared circular dichroism measurement, any of a hydrophobic solvent and a hydrophilic solvent can be used, but preferably, carbon tetrachloride, bichloroform form, methylene dichloride, didimethylsulfoxide, water, etc. Is used. When the target compound is a liquid, it can be measured in neat.

Window plate of the sample cell is either can be used as long as the material that transmits infrared radiation, preferably NaC only anti, BaF ₂ plate is desirable.

A representative flowchart of the method for searching for a superior conformation according to the present invention is shown in FIG. Shown in the figure.

Example

Next, the present invention will be described in more detail by way of examples.

Example 1

In order to perform the conformational analysis of the asymmetric alcohol compound (n is 4) represented by the following chemical structural formula (I), the conformational analysis of the simplified model molecule (n is 2) was first performed. When the correlation between the obtained conformational structure and stability was analyzed, the results shown in Table 1 were obtained.

Table 1 shows that in the stable conformation, the right end has nine appearance patterns of 12, 11 and 31, and the left end has nine appearance patterns of 22, 33, 12 and 13, 23, 31, 21, 32 and 11 Was. On the other hand, it was confirmed that the conformation of 1 was stable in the continuous methylene chain. Therefore, the conformational analysis of the asymmetric alcohol compound (I) (n: 4) was performed using the conformations of 27 (= 3 X 1 X 1 X 9) as the initial structure. Such a result was obtained. Figure 2 shows the predicted VCD spectrum and the measured VCD spectrum derived from these 27 conformations. In Fig. 2, both Since the spectra were in good agreement, which can be an initial structure 729 (= 3 ⁶⁾ can be reduced to conformation 27 conformation, it was divide to explore a stable conformation by this technique.

The four-digit numerical values of the conformations in Table 1 are, from the left, the bond between the hydroxyl group and the methylene group, the bond between the adjacent methylene groups, and the bond between the adjacent methylene group and the methine group. In the bonding position between the adjacent methine group and the methylene group in the ethyl group, 1 means trans conformation, 2 means clockwise Gauche conformation, and 3 means counterclockwise Gauche conformation. . FIG. 3 shows the indexing of the isomer conformational structure of the asymmetric alcohol compound represented by the chemical structural formula (I).

[1]

Correlation between conformation and stability of simplified model molecule (I) (η is 2) for asymmetric alcohol compounds

Conformation AG occupancy

ikcal mol " ¹ )

2212 0 0.112672918

2211 0.25649421 0.073082393

3331 0.263390859 0.072236652

1212 0.378315613 0.059500322

1331 0.549545522 0.044566663

1211 0.557380173 0.043981235

2331 0.648259999 0.037727127

3112 0.664571745 0.036702652

2112 0.665112721 0.036669156

2111 0.738949815 0.03237273

2131 0.739037666 0.032367931

3211 0.746268527 0.031975314

3111 0.758292748 0.031332945

3212 0.808086105 0.028807354

2213 0.851526238 0.026770861

3131 0.856630907 0.026541208

1112 0.937067146 0.023171919

3311 0.961648031 0.02223026

3312 0.971902297 0.02 recitation 836

1213 0.980356928 0.02153928

1111 1 .02212.1672 0.020073273

2231 1 .082439564 0.018130342

1131 1 .198267745 0.014910956

1312 1 .252416587 0.013608653

3213 1 .271630378 0.013174425

1311 1 .328434968 0.011970015

1231 1 .395150388 0.010695305

3333 1 .604343396 0.007513764

3113 1 .749974788 0.005876405

[Table 2] Correlation between conformation and stability of asymmetric alcohol compound (I) (n is 4) Conformation AG Occupancy

(kcal mol " ¹ )

331131 0 0.070238445

331111 0.14395161 0.055088419

211111 0.194699912 0.050566453

221131 0.216656173 0.048726907

221111 0.253004439 0.045827489

331112 0.262177192 0.045123477

221112 0.278889854 0.043868461

231131 0.283948463 0.043495518

311111 0.302233414 0.042173718

321131 0.320069759 0.040923059

131 131 0.32703512 0.040444789

121111 0.366501545 0.037838526

321111 0.36678769 0.037820257

121131 0.405676869 0.035417609

231 112 0.406 120 581 0.0353 stroke 5

211112 0.408188729 0.035267776

311112 0.408697388 0.035237512

131111 0.476292954 0.031438267

231111 0.490809268 0.030677385

311131 0.493669773 0.030529636

0.519201711 0.029241999

131112 0.542877601 0.028096547

211131 0.583473231 0.026235957

111112 0.721708726 0.020776489

321112 0.7268491 0.020597017

121112 0.73827361 0.020203673

111131 0.782404694 0.018753522

Example 2

In order to perform the conformational analysis of the asymmetric alcohol compound (n is 5) represented by the chemical structural formula (I), first, the conformational analysis of the simplified model molecule (n is 2) was performed. Obtained When the correlation between the conformational structure and the stability was analyzed, the same results as in Example 1 in Table 1 were obtained.

Table 1 shows that in the stable conformation, the right end has three appearance patterns of 12, 11, and 31, and the left end has nine appearance patterns of 22, 33, 12, 13, 23, 31, 21, 32, and 11. On the other hand, it was confirmed that the conformation of 1 was stable in the continuous methylene chain. The conformational analysis of the asymmetric alcohol compound (I) (where n is 5) was performed using 27 (= 3X1X1 X1X9) types of conformations as the initial structure, and the results shown in Table 3 were obtained. . Figure 4 shows the predicted VCD spectrum and the measured VCD spectrum derived from these 27 conformations. As shown in Figure 4, since the predicted VCD scan Bae spectrum and measured the VCD scan Bae spectrum was in good agreement, Ru can be reduced to 2187 (= 3 ⁷⁾ conformation 27 conformations allowed in the initial structure I understand.

The four digits of the conformation in Table 1 are, from the left, the bond between the hydroxyl group and the methylene group, the bond between the adjacent methylene groups, and the bond between the adjacent methylene group and the methine group. At the bonding position between the adjacent methine group and the methylene group in the ethyl group, 1 means trans conformation, 2 means clockwise gauche conformation, and 3 means counterclockwise gauche conformation.

[Table 3]

Correlation between conformation and stability of asymmetric alcohol compound (I) (n is 5) Conformation AG Occupancy

(kcal mol " ¹ )

2211131 0 0.075030831

3311131 0.032216301 0.071060072

3311111 0.116296805 0.0616589

2311131 0.175619906 0.055784397

2211111 0.196247666 0.053875693

1211131 0.263982476 0.048055619

3111111 0.290482286 0.045953667

2111111 0.33426278 0.042680516

3211131 0.409042456 0.03761986

2211112 0.4104253 0.03753216

2111112 0.41510163 0.037237102

2311111 0.439349683 0.035743937

1311131 0.440190547 0.035693246

3111112 0.475856709 0.033608043

3111131 0.483939289 0.033152692

1311111 0.510788559 0.031683901

2111131 0.538059014 0.030258666

3311112 0.55768075 0.029273005

3211111 0.605973731 0.026981694

1211111 0.619174408 0.026387199

0.631537171 0.025842323

1111112 0.688420199 0.023476701

3211112 0.690187268 0.023406788

1211112 0.751612276 0.021101733

1111131 0.774074373 0.020316726

2311112 0.793472088 0.019662351

1311112 0.882394836 0.016922179

Example 3

For the analysis of the conformation of (13-(-)-permethrin compound represented by the following chemical structural formula (II), first, the conformation of a simplified model molecule (III) having its cyclic abbreviated structure is shown. Analysis was performed.

(Hi)

3 conformers

3 ~ 2 ~ 2 = 12 conformers

selected 10 conformers When the correlation between the obtained conformational structure and stability was analyzed, it was found that it was represented by one stable conformation. Next, the conformational analysis of the simplified model molecule (IV) having a structure substituted with a phenyl group was performed, and the correlation between the obtained conformational structure and stability was analyzed. A locus has been found. On the other hand, four kinds of conformations were found in the phenoxybenzyl group. Furthermore, the conformational analysis of c / 'i-permethrin compound (II) was performed using the final 10 conformations based on the overall symmetry of the molecule. The results are shown in Table 4. Figure 5 shows the predicted VCD spectrum and the measured VCD spectrum derived from these 10 conformations. As shown in Fig. 5, the spectra of the two matched well, indicating that the 2592 0 3 X 6 X 3 X 6 X 4 X 2) conformation possible as the initial structure can be reduced to 10 conformations. Was.

4] Correlation between conformation and stability of cis ~ ぺ) retrin compound (II)

Conformation AG occupancy

(kcal mol " ¹ )

cp10Ph1 0.495981331 0.079208757

cp10Ph2 0.104941635 0.153249832

cp10Ph3 0.566569617 0.070312565

cp10Ph4 0.5293397 0.074872437

cp20Ph1 0.232690246 0.123527031

cp20Ph2 0.512570625 0.077021766

cp20Ph3 1.329495334 0.019400759

cp20Ph4 0.723214123 0.053977733

cp30P 1 0.05943461 0.165484011

cp30Ph3 0 0.182945109

Industrial applicability

The novel method for searching for a predominant conformation for use in infrared circular dichroic spectrum analysis according to the present invention is omitted by extracting a part of the structure from an optically active molecule. Create a model molecule with a structure, perform a conformational analysis on the model molecular structure, and determine the individual conformational structures indexed from the obtained stereoisomeric relationships including rotational isomerism and their energy values. Statistical analysis of the correlation between the two is to extract the appearance pattern of the stable conformational structure of the model molecule, and to search for the superior conformation of the molecule as a whole. By utilizing this conformational search method, the number of isomeric conformational structures that need to be considered as the initial value can be dramatically reduced compared to the conventional method, and the superior conformation of optically active molecules having a larger molecular weight can be obtained. Locus can be easily and easily searched.

Therefore, the search method according to the present invention can be used as a means of conformational analysis of a compound such as a biological substance or an insecticide having an enormous number of conformations. It is expected to be fully utilized in applications such as the evaluation of the effects of harmful substances on the human body and drug discovery by pharmacological proteomics. The search method according to the present invention can be used as a means of conformational analysis of a compound such as a biological substance or an insecticide having an enormous number of conformations. Therefore, it is expected that the development of the application of harmful substances to humans and the application of pharmacological proteomics to drug discovery will be sufficient.

Claims

The scope of the claims

1. In the method for searching for the predominant conformation of an optically active molecule, the correlation between the isomer conformational structure indexed in advance from the individual stereoisomers of the simplified model molecule of the optically active molecule and its energy value. Is characterized by extracting the appearance pattern of a stable conformational structure, and searching for the dominant conformation of the optically active molecule based on the appearance pattern. Search method.

2. It is characterized by analyzing the infrared circular dichroism spectrum using the appearance pattern of the isomer conformational structure indexed from the individual stereoisomers of the simplified model molecule of the optically active molecule. 3. The method for searching for a superior conformation of an optically active molecule according to claim 1.