CN106372400B - Construct the method and application, the method and system for predicting drug crystal forms of Polarized force field - Google Patents
Construct the method and application, the method and system for predicting drug crystal forms of Polarized force field Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 69
- 239000013078 crystal Substances 0.000 title claims abstract description 38
- 229940079593 drug Drugs 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 title claims abstract description 20
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- 239000011159 matrix material Substances 0.000 claims description 24
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- 238000005457 optimization Methods 0.000 claims description 18
- 230000006698 induction Effects 0.000 claims description 16
- 230000003068 static effect Effects 0.000 claims description 12
- 238000011161 development Methods 0.000 claims description 9
- 230000005684 electric field Effects 0.000 claims description 7
- 230000009471 action Effects 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 230000009881 electrostatic interaction Effects 0.000 claims description 4
- 230000000737 periodic effect Effects 0.000 claims description 4
- 230000036964 tight binding Effects 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 230000005611 electricity Effects 0.000 claims description 3
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- 238000005516 engineering process Methods 0.000 description 2
- SWRGUMCEJHQWEE-UHFFFAOYSA-N ethanedihydrazide Chemical compound NNC(=O)C(=O)NN SWRGUMCEJHQWEE-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
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- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- XEEVLJKYYUVTRC-UHFFFAOYSA-N oxomalonic acid Chemical compound OC(=O)C(=O)C(O)=O XEEVLJKYYUVTRC-UHFFFAOYSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
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Abstract
The invention discloses the method for building Polarized force field and applications, the method and system for predicting drug crystal forms.Wherein, the method for constructing chemical molecular Polarized force field, which is suitable for calculating in equipment in one or more, to be executed.This method includes the following steps.Based on ab initio calculation, calculating is optimized to the quantum chemistry structure of chemical molecular, to obtain the molecular structure of local optimum.The difference of the molecular structure of the local optimum the first energy in neutral charge and the second energy when band makes a reservation for positive valence charge is calculated, and using the difference as the corresponding vertical ion gesture of the molecular structure.Based on the molecular structure of the vertical ion gesture and the local optimum, the Polarized force field parameter of the molecular structure is calculated.The Polarized force field parameter includes the multistage polarizability and frequency dependence polarizability of the multistage vector of atom distribution, atom distribution.Molecular structure based on local optimum and the Polarized force field parameter being calculated, construct corresponding Polarized force field model.
Description
Technical field
The present invention relates to the methods and application, prediction drug of quantum chemistry calculation field, more particularly to building Polarized force field
The method and system of crystal form.
Background technique
Traditional compound design (such as prediction of drug novel crystal forms) lacks mature discovery approach.For example, averagely wanting
A kind of new drug can just be obtained by screening up to ten thousand kinds of compounds.
With high-performance calculation (HPC) and calculate chemical technology development, compound crystal form (especially drug crystal forms)
Prediction more and more attention has been paid to.However, crystal Predicting Technique is current or world-class technical problem.Wherein, the building in the field of force is
The key technique of crystal form prediction.
Currently, about the field of force building can by quantum chemistry Ah initiomethod or application general force field model come
It realizes.Wherein, quantum-mechanical effects method requires a great deal of time, and receives very big limitation in practical application.It is logical
Be with force field model it is approximate according to quantum-mechanical Wo En-Oppenheimer, apply a variety of approximate force field parameters (such as field of force
Parameter can be experience estimated value), computational accuracy is to be improved.
For this purpose, this proposes a kind of new technical solution for constructing Polarized force field and predicting drug crystal forms clearly.
Summary of the invention
For this purpose, the present invention provides the technical solution of a kind of new building Polarized force field and prediction drug crystal forms, it is effective to solve
At least one problem above having determined.
According to an aspect of the present invention, provide it is a kind of construct chemical molecular Polarized force field method, be suitable at one or
It is executed in multiple calculating equipment.This method includes the following steps.Based on ab initio calculation (Ab initio), to chemical molecular
Quantum chemistry structure optimizes calculating, to obtain the molecular structure of local optimum.The molecular structure for calculating the local optimum exists
The difference of the first energy when neutral charge and the second energy when band makes a reservation for positive valence charge, and using the difference as the molecular structure
Corresponding vertical ion gesture.Based on the molecular structure of the vertical ion gesture and the local optimum, the polarization of the molecular structure is calculated
Force field parameter.The Polarized force field parameter includes the multistage polarizability and frequency dependence of the multistage vector of atom distribution, atom distribution
Polarizability.Molecular structure based on local optimum and the Polarized force field parameter being calculated, construct corresponding Polarized force field model.
According to a further aspect of the invention, a kind of method of drug crystal forms prediction is provided, is included the following steps.Root first
The Polarized force field model about drug molecule is constructed according to method of the invention.Then, according to constructed Polarized force field model, meter
Calculate the crystal form of the drug molecule.
According to a further aspect of the invention, a kind of application for constructing chemical molecular Polarized force field is provided, suitable for being distributed in
One or more calculates in equipment.This application include optimization calculation unit, ionic potential computing unit, force field parameter computing unit and
Field of force construction unit.Based on ab initio calculation (Ab initio), optimization calculation unit is suitable for the quantum chemistry knot to chemical molecular
Structure optimizes calculating, to obtain the molecular structure of local optimum.Ionic potential computing unit is suitable for calculating point of the local optimum
The difference of minor structure the first energy in neutral charge and the second energy when band makes a reservation for positive valence charge, and using the difference as point
The corresponding vertical ion gesture of minor structure.Based on the molecular structure of the vertical ion gesture and the local optimum, force field parameter calculates single
Member is suitable for calculating the Polarized force field parameter of the molecular structure.The Polarized force field parameter includes the multistage vector of atom distribution, atom
The multistage polarizability and frequency dependence polarizability of distribution.Field of force construction unit is suitable for molecular structure and calculating based on local optimum
Obtained Polarized force field parameter constructs corresponding Polarized force field model.
Another aspect according to the present invention provides a kind of system of drug crystal forms prediction, including building according to the present invention
The application of chemical molecular Polarized force field and crystal form prediction application.Crystal form prediction application is suitable for according to constructed Polarized force field mould
Type calculates the crystal form of the drug molecule.
To sum up, different from traditional general field of force, the technical solution of building Polarized force field according to the present invention passes through utilization
Ab iitio mode optimizes the partial structurtes of the chemical molecular of standard, and constructs Polarized force field model on this basis,
Available chemical precision more higher than the general field of force.In particular, the scheme in building Polarized force field of the invention is used in
When drug crystal forms predict field, crystal form Predicting Technique scheme can provide accurate crystalline substance based on Polarized force field with high precision
Type design direction, so that the efficiency and success rate of discovery novel crystal forms be greatly improved.
Detailed description of the invention
To the accomplishment of the foregoing and related purposes, certain illustrative sides are described herein in conjunction with following description and drawings
Face, these aspects indicate the various modes that can practice principles disclosed herein, and all aspects and its equivalent aspect
It is intended to fall in the range of theme claimed.Read following detailed description in conjunction with the accompanying drawings, the disclosure it is above-mentioned
And other purposes, feature and advantage will be apparent.Throughout the disclosure, identical appended drawing reference generally refers to identical
Component or element.
Fig. 1 shows the schematic diagram of the calculating environment 100 of some implementation columns according to the present invention；
Fig. 2 shows the schematic diagrames of the application 200 of building chemical molecular Polarized force field according to some embodiments of the invention；
Fig. 3 shows the flow chart of the method 300 of building chemical molecular Polarized force field according to some embodiments of the invention；
Fig. 4 shows the flow chart of the implementation method 400 of step S330 in Fig. 3；And
Fig. 5 shows the flow chart of the implementation method 500 of step S340 in Fig. 3.
Specific embodiment
Exemplary embodiments of the present disclosure are described in more detail below with reference to accompanying drawings.Although showing the disclosure in attached drawing
Exemplary embodiment, it being understood, however, that may be realized in various forms the disclosure without should be by embodiments set forth here
It is limited.On the contrary, these embodiments are provided to facilitate a more thoroughly understanding of the present invention, and can be by the scope of the present disclosure
It is fully disclosed to those skilled in the art.
Fig. 1 shows the schematic diagram of the cloud computing environment 100 of some implementation columns according to the present invention.
As shown in Figure 1, calculating environment 100 includes multiple calculating equipment.Each calculating equipment is an equipment section in cluster
Point.Here, environment 100 is calculated either enterprises lan network environment, is also possible to cloud computing environment (such as in supercomputer
The heart), the present invention does not do excessive limitation to this.Calculating environment 100 for example may include calculate node 110,120,150 and 160, also
It may include memory node 130 and 140, but not limited to this.By taking calculate node 150 and 160 as an example, the two can execute meter respectively
It calculates and applies 151 and 161.It calculates and can be configured as building chemical molecular Polarized force field according to the present invention using 151 and 161
A part of application.In other words, the application of building chemical molecular Polarized force field of the invention, which can be configured as, is calculating environment
The Distributed Application executed in 100.The application of building chemical molecular Polarized force field according to the present invention is carried out below with reference to Fig. 2
It is described in detail.
Fig. 2 shows the schematic diagrames of the application 200 of building chemical molecular Polarized force field according to some embodiments of the invention.
Using 200 for example can be shown in Fig. 1 calculating environment 100 in execute, but not limited to this.
It include optimization calculation unit 210, ionic potential computing unit 220, force field parameter computing unit 230 and power using 200
Field construction unit 240.
Based on ab initio calculation (Ab initio), optimization calculation unit 210 is suitable for the quantum chemistry structure to chemical molecular
Calculating is optimized, to obtain the molecular structure of local optimum.In an embodiment in accordance with the invention, ab initio calculation is by reality
It applies as b3lyp/6-31g (d, p) functional mode.
Wherein, 6-31G (d, p) is the base group for describing atom,
6 be the description to inner orbit, is fitted a slater function (STO) with 6 Gaussian functions (GTO),
31 indicate two groups of STO of virtual orbital to describe, and every group of STO uses 3 and 1 GTO fitting respectively,
D is the polarization function done to non-H atom,
P is the polarization function done to H atom.
In addition, embodiment according to the present invention can also be using a variety of known (except except b31yp/6-31g (d, p) functionals)
Ab iitio mode, the present invention do not do excessive limitation to this.
On the basis of the above, optimization calculation unit 210 can be to the quantum chemistry under known chemical molecular gas phase configuration
Structure carries out local optimum calculating.It is with careless acid dihydrazide (Oxalyl Dihydrazide, molecular formula: C2H6N4O2) below
Example, is illustrated the more specific implementation process of optimization calculation unit 210.
The data instance of the chemical molecular structure to be optimized of careless acid dihydrazide is as follows:
Optimization calculation unit 210 can be configured as using quantum software for calculation (such as Qchem, but not limited to this) calculate
The local optimum structure of chemical molecular.Here, optimization calculation unit 210 in calculating process available chemical molecular in part
A variety of new configurations.Optimization calculation unit 210 can choose low (usually minimum) knot of energy in obtained new configuration
Structure is as local optimum structure.In this way, optimization calculation unit 210 is obtained by above-mentioned calculating and selection by local optimum
Molecular structure.Here, cartesian coordinate data can be represented as by the molecular structure of local optimum, but not limited to this.
For the molecular structure of the local optimum obtained of optimization calculation unit 210, ionic potential computing unit 220 is suitable for meter
Calculate first energy of the molecular structure in neutral charge and the second energy when band makes a reservation for positive valence charge (such as positive 1 valence charge)
The difference of amount, and using the difference as the corresponding vertical ion gesture of the molecular structure.For example, the local optimum of two hydrazides of mesoxalic acid above
The vertical ion gesture of structure is 0.370100.
The part obtained based on the obtained vertical ion gesture of ionic potential computing unit 220 and optimization calculation unit 210 is excellent
The molecular structure of change, force field parameter computing unit 230 are suitable for calculating the Polarized force field parameter of molecular structure.Here, Polarized force field
Parameter includes the multistage polarizability and frequency dependence polarizability of the multistage vector of atom distribution, atom distribution, but not limited to this.
In an embodiment in accordance with the invention, force field parameter computing unit 230 is by the molecular structure comprising local optimum
The data of data (such as cartesian coordinate data of molecular structure) and vertical ion gesture are as input data.For example, the field of force is joined
Number computing unit 230 can apply CamCASP software (Cambridge package for Calculation of
Anisotropic Site Properties calculates Cambridge software package of anisotropy website attribute) it is calculated, but it is unlimited
In this.The input data example of the molecular structure of the local optimum of careless acid dihydrazide is as follows:
The process for calculating 3 kinds of Polarized force field parameters is illustrated in turn below.
The multistage vector of atom distribution is the multiple development of electron density in molecular structure.In one embodiment, the field of force
Parameter calculation unit 230 carries out spherical-harmonic expansion to electron density in molecular structure and obtains multistage vector.According to the present invention
In another embodiment, the multistage vector of the atom distribution for the careless acid dihydrazide that force field parameter computing unit 230 is calculated
Partial data format is as follows:
Multi-stage static polarizability represents the electron density of molecular structure responding ability under the action of an external electric field.Force field parameter
Computing unit 230 can carry out multiple development operation to the function of atom site in the molecular structure is indicated, static more to obtain
Grade polarizability.In an embodiment in accordance with the invention, the original for the careless acid dihydrazide that force field parameter computing unit 230 is calculated
The partial data format of the multistage polarizability of son distribution is as follows:
It should be noted that the response in external electric field of molecule charge is frequency if external electrical field is not steady electric field
It is relevant.By taking careless acid dihydrazide as an example, force field parameter computing unit 230 calculates the frequency dependence multistage pole of resulting atom distribution
Rate partial data format is as follows:
As described above, force field parameter computing unit 230 can be in optimization calculation unit 210 and ionic potential computing unit 220
On the basis of fetched data, high-precision building calculates 3 kinds of force field parameters of Polarized force field model.On this basis, field of force structure
The Polarized force field parameter that unit 240 is suitable for the molecular structure based on local optimum and is calculated is built, corresponding polarization force is constructed
Field model.Here, building Polarized force field is mainly the every energy calculated about molecular structure.Implement at one according to the present invention
In example, the energy calculated of field of force construction unit 240 includes the corresponding multinomial intermolecular lattice energy of molecular crystal of molecular structure
Summation and molecular structure self-energy.
In an embodiment in accordance with the invention, field of force construction unit 240 can use Density functional tight-binding (DFTB)
Mode calculates the self-energy of molecular structure.In addition, embodiment according to the present invention can also be calculated using other well known modes
The self-energy of molecular structure, which is not described herein again.
In addition, field of force construction unit 240 can calculate the molecular structure of local optimum according to above-mentioned Polarized force field parameter
The summation of corresponding molecular crystal, the multinomial intermolecular lattice energy under periodic boundary condition.At one according to the present invention
In embodiment, multinomial intermolecular lattice energy includes the ENERGY E for indicating intermolecular static electrostatic interactionlattice-es, indicate point
Polarize the ENERGY E of interaction between sonlattice-indWith the ENERGY E for indicating intermolecular dispersion interactionlattice-disp。
Wherein, field of force construction unit 240 can calculate E according to following formula (1), (2) and (3)lattice-es。
Wherein,It is that Ewald summation (Ewald summation) under multistage vector is distributed based on atom
Interaction matrix between emptying.In general, the dimension of interaction matrix for example can be 25*25, but not limited to this.A, b are indicatedThe index of two dimensions of matrix.
QtAnd QuThe atom for exactly representing the molecule of two interactions in lattice is distributed multistage vector.What t and u were represented is
The index of multistage vector.N is the index of the cyclic extension of Ewald Summation.K is the vector basis based on reciprocal lattice vector.S square
What the direction type that battle array represents when the atom in lattice in two molecules forms interaction was constituted is spatially steered matrix.F is down
Convergence parameter equation under space.1 is the order of multiple development.It is that multistage lower angstrom watt of vector is distributed based on atom
The real space interaction matrix of Er De summation.R is the vector basis based on real space lattice vector.Expression is
Interaction matrix under construction is between emptying in reciprocal lattice vector kn=0.It is that atom is distributed dimension index in multistage vector
Value when being 0,Indicate self-interaction.It represents in lattice in two molecules
Atom formed interaction when direction arrow constitute be spatially steered matrix.S is based on two atom position structures in molecule
The direction vector made.Ωa, Ωb, it is the vector matrix that two atom positions are constructed based on selected molecule local coordinate system respectively.It is based on the reciprocal lattice vector under between emptying.It is the vector arrow that two atom positions in two molecules are constituted.It is
Real space lattice vector after the extension of real space periodical boundary condition.Convergence letter under between emptying
Number.For the convergent function under the real space.
In addition, indicating the ENERGY E of intermolecular polarization interactionlattice-indIncluding 2 parts, i.e., convergent polarization (induction)
More bodies polarization energy in multistage vector sum lattice.The calculating process of 2 portion of energy is illustrated below.
On the one hand, field of force construction unit 240 it is multistage can to iterate to calculate convergent polarization according to following formula (4) and (5)
Vector.
Wherein,Multistage vector is respectively induced,It is then the multistage polarizability of atom distribution.B ≠ A table
Show and does not have to formula (4) and (5) processing intramolecular polarization interaction.Since intramolecular polarization is processed with DFTB, because
This formula (4) and (5) are for calculating intermolecular polarization interaction.fn(R, β) is Tang-Toennies convergence equation, tool
Body calculation formula are as follows:
R is the vector field homoemorphism between two atom positions.N is convergence order of equation number, and the index of usual order is the model of 1-5
It encloses and is obtained with convergence, but not limited to this.β is a parameter relevant to the property of molecule, can be by constructing three-body group
The mode that cluster is fitted obtains.For example, β may be at the section of [1.2-2.0].
On the other hand, field of force construction unit 240 can be by following calculating operations come bodies more in counting lattice polarization energy.Tool
For body, it is predetermined angstrom of degree (such as 25 that field of force construction unit 240, which is based on molecular structure corresponding molecular crystal construction truncation radius,
Angstrom) cluster.Then, field of force construction unit 240 calculates the induction of the decaying of each atom in the cluster by way of being in harmony certainly
Multistage vectorWith the multistage vector of unattenuated inductionIt is basic herein
On, field of force construction unit 240 calculates the difference of decaying and the multistage vector of unattenuated induction according to formula (6):
In addition, field of force construction unit 240 can be calculated according to formula (7), (8) and (9) induces multistage vectorLattice energy in Ewald sum formula
Formula (7)-(9) parameter declaration refers to the parameter declaration of above formula (1), (2) and (3).
Furthermore field of force construction unit 240 can be according to bodies more in formula (10) counting lattice polarization energy:
240 pairs of the field of force construction unit energy for indicating intermolecular static electrostatic interaction above have been illustrated
Elattice-esCalculating process (utilize formula (1), (2) and (3)) and indicate the intermolecular energy for polarizing and interacting
Elattice-indCalculating process (utilizes formula (4) to (10)).
Continue with the ENERGY E for calculating field of force construction unit 240 and indicating intermolecular dispersion interactionlattice-disp's
Process is illustrated.Field of force construction unit 240 can calculate separately two bulk dispersions can be with three bulk dispersion energy.Specifically, field of force structure
It builds unit 240 and constructs the truncation radius that dispersion can calculate first.For example, truncation radius is 15-25 angstroms, but not limited to this.It is based on
Frequency dependence polarizability, field of force construction unit 250 can calculate abbe number C6 and C8 according to formula (11) and (12).
WhereinWithIt is the frequency dependence polarization of the even grade of induction of the atom from two molecules respectively
Rate,WithIt is the frequency dependence polarizability of the three-level induction three-level of the atom from two molecules respectively.
Based on the abbe number C6 and C8 being calculated, field of force construction unit 240 can calculate two-body according to formula (13)
Dispersion energy:
Wherein, f6And f8Indicate above it is stated that Tang-Toennies restrain equation.6 and 8 be convergent order.
RabIt is the distance of the atom interdigit in two molecules.
Field of force construction unit 240 can calculate three-body abbe number C9 according to formula (14).
Indicate that three not homoatomic even grades induce even grade in two molecules
Frequency dependence polarizability.
Based on the three-body abbe number C9 being calculated, field of force construction unit 240 can calculate three-body according to formula (15)
Dispersion energy.
Wherein A, B and C refer to that three molecules, a, b and c refer to the atom in molecule,Refer to that three atoms form triangle
The angle at three angles later.
By taking careless acid dihydrazide as an example, Polarized force field result constructed by application 200 of the invention is as follows:
QM 1-body=-896.247339368hartrees
QM 2-body=-0.142601938hartrees
MM full=-763.941kJ/mol
MM 1-body=0.000kJ/mol
MM 2-body=-775.516kJ/mol
MM many-body=11.576kJ/mol
QM 1+2-body energy=-896.389941306hartrees
MM many-body energy=11.576kJ/mol (5.788kJ/mol per monomer)
HMBI Energy=-896.385532326hartrees
The above results show that the reference energy of experiment is -896.3934378hartrees, and error reaches in several kJ/mol
Chemical precision.
To sum up, different from traditional general field of force, the application 200 of building Polarized force field according to the present invention by using from
Head calculation optimizes the partial structurtes of the chemical molecular of standard, and constructs Polarized force field model on this basis, can
To obtain chemical precision more higher than the general field of force.In particular, when application 200 is used in drug crystal forms prediction field, it is brilliant
Type Predicting Technique scheme can provide accurate crystal form design direction, to greatly mention based on Polarized force field with high precision
The efficiency and success rate of high discovery novel crystal forms.
Fig. 3 shows the flow chart of the method 300 of building chemical molecular Polarized force field according to some embodiments of the invention.
Method 300, which is suitable for calculating in equipment in one or more, to be executed.In other words, method 300 can be in cloud computing environment or internal collection
It is executed in group.
As shown in figure 3, method 300 starts from step S310.In step s310, it is based on ab initio calculation (Ab initio),
Calculating is optimized to the quantum chemistry structure of chemical molecular, to obtain the molecular structure of local optimum.One according to the present invention
Embodiment, step S310 can use b31yp/6-31g (d, p) functional mode, to the quantum chemistry structure of the chemical molecular into
Row optimization calculates, and will calculate the low molecular structure of resulting local energy as the molecular structure of the local optimum.Step
The more specific embodiment of S310 is consistent with above optimization calculation unit 210, and which is not described herein again.
After the molecular structure for obtaining local optimum in step s310, method 300 executes step S320.In step S320
In, it calculates first energy of the molecular structure of local optimum in neutral charge and makes a reservation for positive valence charge (such as positive 1 valence electricity in band
Lotus) when the second energy difference, and using the difference as the corresponding vertical ion gesture of the molecular structure.
Molecular structure and step S320 based on local optimum obtained in step S310 calculate gained vertical ion gesture, side
Method 300 executes step S330.In step S330, the Polarized force field parameter of molecular structure is calculated.Here, Polarized force field parameter example
It such as may include the multistage polarizability and frequency dependence polarizability that multistage vector, the atom of atom distribution are distributed.According to the present invention
One embodiment, step S330 may be implemented as method 400 as shown in Figure 4.
As shown in figure 4, method 400 starts from step S410, spherical-harmonic expansion is carried out to electron density in the molecular structure,
To obtain the multistage vector of atom distribution.Method 400 further includes step S420, to the letter for indicating atom site in molecular structure
Number carries out multiple development operations, to obtain the multistage for representing the electron density of molecular structure responding ability under the action of an external electric field
Polarizability.In addition, method 400 also executes step S430, the frequency dependence polarizability of atom distribution in molecular structure is obtained.Step
The more specific embodiment of S330 is consistent with above force field parameter computing unit 230, and which is not described herein again.
Polarized force field parameter obtained by molecular structure and step S330 based on local optimum obtained by step S310, method 300
Execute step S340.In step S340, the corresponding Polarized force field model of analysis structure of local optimum is constructed.Specifically, exist
The self-energy of the molecular structure of local optimum is calculated in step S340 using Density functional tight-binding (DFTB) mode.In addition,
In step S340 according to Polarized force field parameter calculate local optimum molecular structure corresponding to molecular crystal, in periodic boundary
Under the conditions of multinomial intermolecular lattice energy summation.
In an embodiment in accordance with the invention, multinomial intermolecular lattice energy includes indicating intermolecular static electrostatic phase interaction
ENERGY Elattice-es, indicate it is intermolecular polarization interaction ENERGY Elattice-indWith the intermolecular dispersion interaction of expression
ENERGY Elattice-disp.Step S340 may be implemented as method 500 shown in fig. 5.
As shown in figure 5, method 500 starts from step S510.In step S510, according to atom be distributed multistage vector, with
And in lattice the mutual molecule of any two position coordinates, calculate the energy for indicating intermolecular static electrostatic interaction
Elattice-es.Here, step S510 can calculate E according to above formula (1), (2) and (3)lattice-es, which is not described herein again.
Method 500 further includes step S520, calculates the energy for indicating intermolecular polarization interaction.Here, molecule is indicated
Between polarize the ENERGY E of interactionlattice-indEnergy include 2 parts, i.e. convergent polarization (induction) multistage vector sum lattice
Interior more body polarization energy.Step S520 can calculate the multistage vector of convergent polarization according to above formula (4) and (5), here not
It repeats again.Step S520 can be according to bodies more in above formula (6) to (10) counting lattice polarization energy, and which is not described herein again.
Method 500 further includes step S530, calculates the ENERGY E for indicating intermolecular dispersion interactionlattice-disp.According to
One embodiment of the invention, step S530 calculates separately two bulk dispersions can be with three bulk dispersion energy.In order to calculate two bulk dispersion energy,
The truncation radius that dispersion can calculate, such as 15-25 angstroms are constructed in step S530 first.Then, step S530 can be according to above
Middle formula (11), (12) and (13) calculates two bulk dispersion energy, and which is not described herein again.In addition, step S530 can be according to above
Formula (14) and (15) calculate three bulk dispersion energy, and which is not described herein again.It should be noted that the more specific embodiment of step S340 can be with
Middle field of force construction unit 240 is seen above, which is not described herein again.
In the instructions provided here, numerous specific details are set forth.It is to be appreciated, however, that implementation of the invention
Example can be practiced without these specific details.In some instances, well known method, knot is not been shown in detail
Structure and technology, so as not to obscure the understanding of this specification.
Similarly, it should be understood that in order to simplify the disclosure and help to understand one or more of the various inventive aspects,
Above in the description of exemplary embodiment of the present invention, each feature of the invention is grouped together into single implementation sometimes
In example, figure or descriptions thereof.However, the disclosed method should not be interpreted as reflecting the following intention: i.e. required to protect
Shield the present invention claims than feature more features expressly recited in each claim.More precisely, as following
As claims reflect, inventive aspect is all features less than single embodiment disclosed above.Therefore, it abides by
Thus the claims for following specific embodiment are expressly incorporated in the specific embodiment, wherein each claim itself
As a separate embodiment of the present invention.
Those skilled in the art should understand that the module of the equipment in example disclosed herein or unit or groups
Part can be arranged in equipment as depicted in this embodiment, or alternatively can be positioned at and the equipment in the example
In different one or more equipment.Module in aforementioned exemplary can be combined into a module or furthermore be segmented into multiple
Submodule.
Those skilled in the art will understand that can be carried out adaptively to the module in the equipment in embodiment
Change and they are arranged in one or more devices different from this embodiment.It can be the module or list in embodiment
Member or component are combined into a module or unit or component, and furthermore they can be divided into multiple submodule or subelement or
Sub-component.Other than such feature and/or at least some of process or unit exclude each other, it can use any
Combination is to all features disclosed in this specification (including adjoint claim, abstract and attached drawing) and so disclosed
All process or units of what method or apparatus are combined.Unless expressly stated otherwise, this specification is (including adjoint power
Benefit require, abstract and attached drawing) disclosed in each feature can carry out generation with an alternative feature that provides the same, equivalent, or similar purpose
It replaces.
In addition, it will be appreciated by those of skill in the art that although some embodiments described herein include other embodiments
In included certain features rather than other feature, but the combination of the feature of different embodiments mean it is of the invention
Within the scope of and form different embodiments.For example, in the following claims, embodiment claimed is appointed
Meaning one of can in any combination mode come using.
In addition, be described as herein can be by the processor of computer system or by executing by some in the embodiment
The combination of method or method element that other devices of the function are implemented.Therefore, have for implementing the method or method
The processor of the necessary instruction of element forms the device for implementing this method or method element.In addition, Installation practice
Element described in this is the example of following device: the device be used for implement as in order to implement the purpose of the invention element performed by
Function.
As used in this, unless specifically stated, come using ordinal number " first ", " second ", " third " etc.
Description plain objects, which are merely representative of, is related to the different instances of similar object, and is not intended to imply that the object being described in this way must
Must have the time it is upper, spatially, sequence aspect or given sequence in any other manner.
Although the embodiment according to limited quantity describes the present invention, above description, the art are benefited from
It is interior it is clear for the skilled person that in the scope of the present invention thus described, it can be envisaged that other embodiments.Additionally, it should be noted that
Language used in this specification primarily to readable and introduction purpose and select, rather than in order to explain or limit
Determine subject of the present invention and selects.Therefore, without departing from the scope and spirit of the appended claims, for this
Many modifications and changes are obvious for the those of ordinary skill of technical field.For the scope of the present invention, to this
Invent done disclosure be it is illustrative and not restrictive, it is intended that the scope of the present invention be defined by the claims appended hereto.
Claims (22)
1. a kind of method for constructing chemical molecular Polarized force field, executes, this method packet suitable for calculating in equipment in one or more
It includes:
Based on ab initio calculation (Ab initio), calculating is optimized to the quantum chemistry structure of chemical molecular, to obtain part
The molecular structure of optimization；
Calculate first energy of the molecular structure of the local optimum in neutral charge and second when band makes a reservation for positive valence charge
The difference of energy, and using the difference as the corresponding vertical ion gesture of the molecular structure；
Based on the molecular structure of the vertical ion gesture and the local optimum, the Polarized force field parameter of the molecular structure, the pole are calculated
Change the multistage polarizability and frequency dependence polarizability that force field parameter includes the multistage vector of atom distribution, atom distribution；And
Molecular structure based on local optimum and the Polarized force field parameter being calculated, construct corresponding Polarized force field model.
2. the method for claim 1, wherein described be based on ab initio calculation (Ab initio), to the amount of chemical molecular
The step of sub- chemical structure optimizes calculating, molecular structure to obtain local optimum include:
In the way of b3lyp/6-31g (d, p) functional, calculating is optimized to the quantum chemistry structure of the chemical molecular, and will
Calculate molecular structure of the low molecular structure of resulting local energy as the local optimum.
3. method according to claim 1 or 2, wherein it is described to be based on the vertical ion gesture, calculate the polarization of the molecular structure
Force field parameter, the Polarized force field parameter include the multistage polarizability and frequency dependence of the multistage vector of atom distribution, atom distribution
The step of polarizability includes:
Spherical-harmonic expansion is carried out to electron density in the molecular structure, to obtain the multistage vector of atom distribution；
Multiple development operation is carried out to the function for indicating atom site in the molecular structure, to obtain the electricity for representing the molecular structure
The multistage polarizability of sub- density responding ability under the action of an external electric field；And
Obtain the frequency dependence polarizability that atom is distributed in the molecular structure.
4. the method for claim 1, wherein molecular structure based on local optimum and the polarization force being calculated
Field parameters, the step of constructing corresponding Polarized force field model include:
The self-energy of the molecular structure of the local optimum is calculated using Density functional tight-binding (DFTB) mode；
Molecular crystal corresponding to the molecular structure of the local optimum is calculated, on periodical side according to the Polarized force field parameter
The summation of multinomial intermolecular lattice energy under the conditions of boundary.
5. method as claimed in claim 4, wherein the multinomial intermolecular lattice energy includes indicating intermolecular static electrostatic phase
The ENERGY E of interactionlattice-es, indicate it is intermolecular polarization interaction ENERGY Elattice-indIt is mutual with the intermolecular dispersion of expression
The ENERGY E of effectlattice-disp, described to be calculated corresponding to the molecular structure of the local optimum according to the Polarized force field parameter
Multinomial intermolecular lattice energy of the molecular crystal under periodic boundary condition summation the step of include:
According to the position coordinates of the mutual molecule of any two in the multistage vector and lattice of atom distribution, computational chart
Show the ENERGY E of intermolecular static electrostatic interactionlattice-es；
Calculate the ENERGY E for indicating intermolecular polarization interactionlattice-ind；And
Calculate the ENERGY E for indicating intermolecular dispersion interactionlattice-disp。
6. method as claimed in claim 5, wherein described to calculate the energy for indicating intermolecular static electrostatic interaction
Elattice-esThe step of include following manner:
Wherein,It is the emptying that Ewald summation (Ewald summation) under multistage vector is distributed based on atom
Between interaction matrix, a and b are indicatedThe index of two dimensions of matrix, QtAnd QuTwo are exactly represented in lattice
The atom of the molecule of interaction is distributed multistage vector, and what t and u were represented is the index of multistage vector, and N is Ewald
The index of the cyclic extension of Summation, K are the vector basis based on reciprocal lattice vector, and s-matrix represents in lattice in two molecules
What direction type when atom forms interaction was constituted is spatially steered matrix, f be between emptying under convergence parameter equation, I is
The order of multiple development,Convergent function under between emptying,It is multistage based on atom distribution
The real space interaction matrix that Ewald is summed under vector, r is the vector basis based on real space lattice vector,Expression is the interaction matrix under constructing between emptying in reciprocal lattice vector kn=0,It is atom point
Value when dimension index is 0 in cloth multistage vector,Indicate self-interaction,It represents
What the direction arrow when atom in lattice in two molecules forms interaction was constituted is spatially steered matrix, and S is to be based on
The direction vector of two atom positions construction in molecule, ΩaAnd ΩbIt is that two atom positions are sat based on selected molecule local respectively
The vector matrix of series structure is marked,Be based on the reciprocal lattice vector under between emptying,It is two atom positions in two molecules
The vector arrow of composition,It is then the real space lattice vector after the extension of real space periodical boundary condition,For the convergent function under the real space.
7. such as method described in claim 5 or 6, wherein described to calculate the energy for indicating intermolecular polarization interaction
Elattice-indThe step of include:
The multistage vector of convergent polarization is iterated to calculate according to following formula:
Multistage vector is respectively induced,It is then the multistage polarizability of atom distribution, fn(R, β) is indicated
Tang-Toennies restrains equation；With
According to bodies more in following manner counting lattice polarization energy:
It is the cluster of predetermined angstrom of degree based on corresponding molecular crystal construction truncation radius, and calculates the group by way of being in harmony certainly
The induction multistage vector of the decaying of each atom in clusterWith the multistage vector of unattenuated induction
The difference of decaying and the multistage vector of unattenuated induction is calculated according to following manner:
It is calculated according to following manner and induces multistage vectorLattice in Ewald sum formula
Energy
According to bodies more in following formula counting lattices polarization energy:
8. method as claimed in claim 5, wherein described to calculate the energy for indicating intermolecular dispersion interaction
Elattice-dispThe step of include:
Calculate two bulk dispersion energy；
Calculate three bulk dispersion energy.
9. method according to claim 8, wherein the step of two bulk dispersion energy of the calculating includes:
The truncation radius that building dispersion can calculate；
Abbe number C6 and C8 are calculated based on the frequency dependence polarizability, and according to following manner:
Wherein,WithRespectively indicate the frequency dependence polarization of the even grade of induction of the atom from two molecules
Rate,WithThe frequency dependence polarizability of the three-level induction three-level of the atom from two molecules is respectively indicated,
Two bulk dispersion energy are calculated based on abbe number C6 and C8, and according to following formula:
Wherein, f6And f8Indicate that Tang-Toennies restrains equation, 6 and 8 be convergent order, RabIt indicates in two molecules
Atom interdigit distance.
10. method as claimed in claim 9, wherein calculate three bulk dispersion energy the step of include:
Three-body abbe number C9 is calculated according to following formula:
Wherein,Indicate that three not homoatomic even grades induce even grade in two molecules
Frequency dependence polarizability；
Based on the three-body abbe number C9 being calculated, three bulk dispersion energy are calculated according to following manner:
Wherein, A, B and C refer to that three molecules, a, b and c refer to the atom in molecule,WithIndicate that three atoms form triangle
The angle at three angles later.
11. a kind of method of drug crystal forms prediction, comprising:
According to method such as of any of claims 1-10, the Polarized force field model about drug molecule is constructed；
According to constructed Polarized force field model, the crystal form of the drug molecule is calculated.
12. a kind of application for constructing chemical molecular Polarized force field, suitable for being distributed in one or more calculating equipment, the application packet
It includes:
Optimization calculation unit is based on ab initio calculation (Ab initio), is carried out suitable for the quantum chemistry structure to chemical molecular excellent
Change and calculate, to obtain the molecular structure of local optimum；
Ionic potential computing unit, suitable for calculate first energy of the molecular structure of the local optimum in neutral charge and in band it is pre-
The difference of the second energy when fixed positive valence charge, and using the difference as the corresponding vertical ion gesture of the molecular structure；
Force field parameter computing unit is suitable for calculating the molecule knot based on the molecular structure of the vertical ion gesture and the local optimum
The Polarized force field parameter of structure, the Polarized force field parameter include atom distribution multistage vector, atom distribution multistage polarizability and
Frequency dependence polarizability；And
Field of force construction unit, suitable for the molecular structure based on local optimum and the Polarized force field parameter being calculated, building is corresponding
Polarized force field model.
13. application as claimed in claim 12, wherein the optimization calculation unit is suitable for according to following manner based on from the beginning
Algorithm (Ab initio) optimizes calculating to the quantum chemistry structure of chemical molecular, to obtain the molecule knot of local optimum
Structure:
In the way of b3lyp/6-31g (d, p) functional, calculating is optimized to the quantum chemistry structure of the chemical molecular, and will
Calculate molecular structure of the low molecular structure of resulting local energy as the local optimum.
14. application as described in claim 12 or 13, wherein the force field parameter computing unit is suitable for according to following manner meter
Calculate the Polarized force field parameter of the molecular structure:
Spherical-harmonic expansion is carried out to electron density in the molecular structure, to obtain the multistage vector of atom distribution；
Multiple development operation is carried out to the function for indicating atom site in the molecular structure, to obtain the electricity for representing the molecular structure
Sub- density under the action of an external electric field responding ability atom distribution multistage polarizability；And
Obtain the frequency dependence polarizability that atom is distributed in the molecular structure.
15. application as claimed in claim 12, wherein the molecular structure based on local optimum and the polarization being calculated
Force field parameter, the step of constructing corresponding Polarized force field model include:
The self-energy of the molecular structure of the local optimum is calculated using Density functional tight-binding (DFTB) mode；
Molecular crystal corresponding to the molecular structure of the local optimum is calculated, on periodical side according to the Polarized force field parameter
The summation of multinomial intermolecular lattice energy under the conditions of boundary.
16. application described in claim 15, wherein the multinomial intermolecular lattice energy includes indicating intermolecular static electrostatic phase
The ENERGY E of interactionlattice-es, indicate it is intermolecular polarization interaction ENERGY Elattice-indIt is mutual with the intermolecular dispersion of expression
The ENERGY E of effectlattice-disp, described to be calculated corresponding to the molecular structure of the local optimum according to the Polarized force field parameter
Multinomial intermolecular lattice energy of the molecular crystal under periodic boundary condition summation the step of include:
According to the position coordinates of the mutual molecule of any two in the multistage vector and lattice of atom distribution, computational chart
Show the ENERGY E of intermolecular static electrostatic interactionlattice-es；
Calculate the ENERGY E for indicating intermolecular polarization interactionlattice-ind；And
Calculate the ENERGY E for indicating intermolecular dispersion interactionlattice-disp。
17. application as claimed in claim 16, wherein described to calculate the energy for indicating intermolecular static electrostatic interaction
Elattice-esThe step of include following manner:
Wherein,It is the emptying that Ewald summation (Ewald summation) under multistage vector is distributed based on atom
Between interaction matrix, a, b indicateThe index of two dimensions of matrix, QtAnd QuExactly represent two phases in lattice
The atom of the molecule of interaction is distributed multistage vector, and what t and u were represented is the index of multistage vector, and N is Ewald Summation
Cyclic extension index, K is the vector basis based on reciprocal lattice vector, and the atom that s-matrix represents in lattice in two molecules is formed
What direction type when interaction was constituted be spatially steered matrix, f be between emptying under convergence parameter equation, I is multiple development
Order,Convergent function under between emptying,It is that multistage lower angstrom of vector is distributed based on atom
The real space interaction matrix of Grindelwald summation, r is the vector basis based on real space lattice vector,It indicates
It is the interaction matrix under being constructed between emptying in reciprocal lattice vector kn=0,It is that atom is distributed dimension rope in multistage vector
Value when being cited as 0,Indicate self-interaction,It represents in lattice from two molecules
In atom formed interaction when direction arrow constitute be spatially steered matrix, S is based on two atom positions in molecule
The direction vector of construction, ΩaAnd ΩbIt is the vector matrix that two atom positions are constructed based on selected molecule local coordinate system respectively,Based on the reciprocal lattice vector under between emptying,It is the vector arrow that two atom positions in two molecules are constituted,Be then
Real space lattice vector after the extension of real space periodical boundary condition,For the convergence letter under the real space
Number.
18. the application as described in claim 16 or 17, wherein described to calculate the energy for indicating intermolecular polarization interaction
Elattice-indThe step of include:
The multistage vector of convergent polarization is iterated to calculate according to following formula:
Multistage vector is respectively induced,It is then the multistage polarizability of atom distribution, fn(R, β) is indicated
Tang-Toennies restrains equation；With
According to bodies more in following manner counting lattice polarization energy:
It is the cluster of predetermined angstrom of degree based on corresponding molecular crystal construction truncation radius, and calculates the group by way of being in harmony certainly
The induction multistage vector of the decaying of each atom in clusterWith the multistage vector of unattenuated induction
The difference of decaying and the multistage vector of unattenuated induction is calculated according to following manner:
It is calculated according to following manner and induces multistage vectorLattice energy in Ewald sum formula
According to bodies more in following formula counting lattices polarization energy:
19. application as claimed in claim 16, wherein described to calculate the energy for indicating intermolecular dispersion interaction
Elattice-dispThe step of include:
Calculate two bulk dispersion energy；
Calculate three bulk dispersion energy.
20. application as claimed in claim 19, wherein the step of two bulk dispersion energy of the calculating includes:
The truncation radius that building dispersion can calculate；
Abbe number C6 and C8 are calculated based on the frequency dependence polarizability, and according to following manner:
WhereinWithThe frequency dependence polarizability of the even grade of induction of the atom from two molecules is respectively indicated,WithThe frequency dependence polarizability of the three-level induction three-level of the atom from two molecules is respectively indicated,
Two bulk dispersion energy are calculated based on abbe number C6 and C8, and according to following formula:
Wherein, f6And f8Indicate that Tang-Toennies restrains equation, 6 and 8 be convergent order, RabIt indicates in two molecules
Atom interdigit distance.
21. application as claimed in claim 20, wherein the step of calculating three bulk dispersion energy include:
Three-body abbe number C9 is calculated according to following formula:
Wherein,Indicate that three not homoatomic even grades induce even grade in two molecules
Frequency dependence polarizability；
Based on the three-body abbe number C9 being calculated, three bulk dispersion energy are calculated according to following manner:
Wherein A, B and C refer to that three molecules, a, b and c refer to the atom in molecule,Refer to that three atoms form triangle
The angle at three angles later.
22. a kind of system of drug crystal forms prediction, comprising:
According to the application for constructing chemical molecular Polarized force field as described in any one of claim 12-21；And
Crystal form prediction application, suitable for calculating the crystal form of the drug molecule according to constructed Polarized force field model.
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