JP6623697B2 - Method and apparatus for calculating interaction energy, and program - Google Patents

Description

  The present invention relates to a method and apparatus for calculating an interaction energy between a target molecule and a drug candidate molecule, and a program for executing the method.

  When a certain protein has a functional site that has an adverse effect on the body, in drug discovery targeting the protein, it is necessary to design a ligand that stably binds to the functional site of the protein. The functional site of the protein is closed by the stable binding of the ligand to the protein. As a result, adverse effects on the body by the protein are suppressed.

In order to determine whether the binding between a protein and a ligand is stable, a technique is generally used to determine the interaction energy between the protein and the ligand with high accuracy by a technique based on quantum mechanical (QM). (For example, see Non-Patent Document 1).
The method based on QM has a problem that the calculation time increases exponentially as the number of atoms to be calculated increases. In the case of only a complex of a protein and a ligand, even if the number of atoms is several thousand, the number of atoms can be tens of thousands if water molecules existing around are included. Therefore, performing the QM calculation including the water molecule has a problem in terms of calculation time.

Therefore, a method of specifying a water molecule that affects the interaction between a protein and a ligand and explicitly considering only the specified water molecule is effective in terms of calculation time. As a method for specifying a water molecule, a method using an X-ray crystal structure of a protein and a molecular dynamics (MD) calculation has been proposed (for example, see Non-Patent Documents 2 and 3).
However, the proposed method may not be able to reproduce the position of the water molecule existing in the crystal structure.

  Therefore, there is a need for a method of calculating interaction energy that can appropriately select the water molecule to be considered and that can shorten the calculation time by appropriately selecting the water molecule to be considered.

The Fragment Molecular Orbital Method: Practical Applications to Large Molecular Systems. , CRC Press (2009) ISBN / ISSN: 14200778488 Abel R, Young T, Farid R, Berne BJ, and Friesner RA. The role of the active-site solvent in the thermodynamics of factor X alilig binding. J Am Chem Soc, 130: 2817-2831, 2008. Young T, Abel R, Kim B, Berne BJ, and Friesner RA. Motifs for molecular recognition exploiting hydrophobic enclosure in protein-ligand binding. PNAS, 104: 808-813, 2007.

  It is an object of the present invention to solve the above-mentioned problems in the related art and achieve the following objects. That is, an object of the present invention is to provide a method and apparatus for calculating an interaction energy capable of appropriately selecting a water molecule to be considered and shortening the calculation time, and a program for executing the calculation method. I do.

The means for solving the above problems are as follows. That is,
The calculation method of the disclosed interaction energy is:
Using a computer, the interaction energy between the target molecule and the drug candidate molecule is calculated, a method for calculating the interaction energy,
Performing a first molecular dynamics calculation using the target molecule, the drug candidate molecule, and a plurality of water molecules around the target molecule and the drug candidate molecule;
At least one representative structure representing the time change of the structure of the complex is determined based on the time change of the structure of the complex of the target molecule and the drug candidate molecule obtained by the first molecular dynamics calculation. The process of
Performing a second molecular dynamics calculation while constraining the drug candidate molecule for the representative structure, and constraining a partial structure relatively distant from the drug candidate molecule in the target molecule;
Extracting a water molecule using the result of the second molecular dynamics calculation;
In consideration of the extracted water molecules, the target molecule, the step of calculating the interaction energy of the drug candidate molecule,
including.

The disclosed program is stored on a computer
Performing a first molecular dynamics calculation using a target molecule, a drug candidate molecule, and a plurality of water molecules around the target molecule and the drug candidate molecule;
At least one representative structure representing the time change of the structure of the complex is determined based on the time change of the structure of the complex of the target molecule and the drug candidate molecule obtained by the first molecular dynamics calculation. The process of
Performing a second molecular dynamics calculation while constraining the drug candidate molecule for the representative structure, and constraining a partial structure relatively distant from the drug candidate molecule in the target molecule;
Extracting a water molecule using the result of the second molecular dynamics calculation;
In consideration of the extracted water molecules, the target molecule, the step of calculating the interaction energy of the drug candidate molecule,
Is executed.

The disclosed interaction energy calculation device includes:
A first MD calculation unit that performs a first molecular dynamics calculation using a target molecule, a drug candidate molecule, and a plurality of water molecules around the target molecule and the drug candidate molecule;
At least one representative structure representing the time change of the structure of the complex is determined based on the time change of the structure of the complex of the target molecule and the drug candidate molecule obtained by the first molecular dynamics calculation. A representative structure determining unit,
A second MD calculation unit that performs a second molecular dynamics calculation while constraining the drug candidate molecule for the representative structure, and constraining a partial structure relatively far from the drug candidate molecule in the target molecule;
A water molecule extraction unit that extracts a water molecule using the result of the second molecular dynamics calculation;
In consideration of the extracted water molecules, the target molecule, a calculation unit that calculates the interaction energy of the drug candidate molecule,
Is provided.

According to the disclosed calculation method of interaction energy, the above-mentioned conventional problems can be solved, the object can be achieved, water molecules to be considered can be appropriately selected, and the calculation time can be reduced. A method for calculating energy can be provided.
According to the disclosed program, it is possible to provide a program that can solve the above-described various problems in the related art, achieve the above object, appropriately select a water molecule to be considered, and reduce the calculation time.
According to the disclosed interaction energy calculation device, the above-mentioned conventional problems can be solved, the above-mentioned object can be achieved, the water molecule to be considered can be appropriately selected, and the calculation time can be reduced. An energy calculation device can be provided.

FIG. 1 is a flowchart illustrating an example of the disclosed interaction energy calculation method. FIG. 2 is a flowchart of another example for explaining the disclosed interaction energy calculation method. FIG. 3 is a configuration example of the disclosed interaction energy calculation device. FIG. 4 is another configuration example of the disclosed interaction energy calculation device. FIG. 5 is another configuration example of the disclosed interaction energy calculation device. FIG. 6 is a diagram showing the results of Example 1. FIG. 7 is a diagram showing the results of Comparative Example 1.

Drug discovery refers to the process of designing a drug. The drug discovery is performed, for example, in the following order.
(1) Determination of target molecule (2) Search for lead compounds, etc. (3) Assay for physiological effects (4) Safety / toxicity test In search for lead compounds, etc. (lead compounds and compounds derived therefrom), many drugs are used. It is important to accurately evaluate the interaction between each of the candidate molecules and the target molecule.

  The process of designing a drug using a computer is sometimes referred to as IT drug discovery. The technology of IT drug discovery is available for drug discovery in general. Among them, utilizing the technology of IT drug discovery to search for lead compounds and the like is useful in increasing the period and probability of new drug development.

  The disclosed technology can be used, for example, for searching for a lead compound or the like expected to have high pharmacological activity.

(Method of calculating interaction energy)
The disclosed method for calculating interaction energy is a method for calculating interaction energy in which the computer calculates the interaction energy between a target molecule and a drug candidate molecule.
The method for calculating the interaction energy includes a first MD calculation step, a representative structure determination step, a second MD calculation step, a water molecule extraction step, and an interaction energy calculation step. And other steps.

  The method for calculating the interaction energy is performed using a computer. The computer used for the method for calculating the interaction energy may be one computer or a plurality of computers. For example, the calculation method of the interaction energy may be executed in a distributed manner by a plurality of computers.

As described above, in the prior art using the X-ray crystal structure of a protein and the molecular dynamics (MD) calculation, the position of a water molecule existing in the crystal structure may not be able to be reproduced. In this regard, the present inventors considered the cause as follows.
The positional relationship between the protein and the ligand in the crystal structure obtained by the X-ray crystal structure analysis corresponds to only one pattern among a plurality of actually possible positional relationships. On the other hand, when the structure of the complex of the protein and the ligand is slightly fluctuating from the crystal structure, the conventional art may not be able to reproduce the position of the water molecule existing in the crystal structure. Thought.

  Therefore, the present inventor thinks that the problem of the prior art can be solved by grasping all the patterns of the positional relationship (complex) between the target molecule and the drug candidate molecule and selecting an appropriate pattern from the patterns. , And the disclosed technology was completed.

FIG. 1 is a flowchart for explaining the method for calculating the interaction energy.
In this flowchart, first, the first MD calculation step is performed. In this step, a first molecular dynamics calculation is performed using a target molecule, a drug candidate molecule, and a plurality of water molecules around the target molecule and the drug candidate molecule.
Next, the representative structure determination step is performed. In this step, based on the time change of the structure of the complex of the target molecule and the drug candidate molecule, which is obtained by the first molecular dynamics calculation, one or more representative of the time change of the structure of the complex Determine the representative structure.
Next, the second MD calculation step is performed. In this step, a second molecular dynamics calculation is performed on the representative structure while restricting the drug candidate molecule and restricting a partial structure of the target molecule relatively distant from the drug candidate molecule.
Next, a water molecule extraction step is performed. In this step, water molecules are extracted using the result of the second molecular dynamics calculation.
Next, the interaction energy calculation step (interaction Eg calculation step) is performed. In this step, the interaction energy between the target molecule and the drug candidate molecule is calculated in consideration of the extracted water molecule.

<First MD calculation step>
In the first MD calculation step, a first molecular dynamics calculation is performed using a target molecule, a drug candidate molecule, and a plurality of water molecules around the target molecule and the drug candidate molecule.

  The number of the plurality of water molecules is not particularly limited, and can be appropriately selected depending on the purpose. The water molecules are arranged at a normal density around the target molecule and the drug candidate molecule, for example. There is no particular limitation on how far the water molecule is located from the target molecule and the drug candidate molecule, and it can be appropriately selected according to the purpose. For example, the water molecules may be arranged up to a limit position at which an interaction between the arranged water molecule, the target molecule and the drug candidate molecule occurs. The interaction here means a non-bonding interaction, for example, an electrostatic interaction, a Van der Waals interaction, and the like.

It is preferable that the first molecular dynamics calculation is performed with the drug candidate molecule restricted, since this leads to prevention of large-scale structural deformation.
The restriction of the drug candidate molecule may be performed on all atoms constituting the drug candidate molecule, or may be performed on all heavy atoms constituting the drug candidate molecule, or the drug candidate It may be carried out for one heavy atom constituting the molecule. Here, in this specification, a heavy atom means an atom other than a hydrogen atom.
As a method of the constraint, for example, a method of applying a force to the atom to be bound so as to return to a specific coordinate when the atom moves, and the like can be mentioned.

  The target molecule is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include proteins, RNA (ribonucleic acid), DNA (deoxyribonucleic acid, deoxyribonucleic acid), and the like.

  The first molecular dynamics calculation can be performed using a molecular dynamics calculation program. Examples of the molecular dynamics calculation program include AMBER, CHARMm, GROMACS, GROMOS, NAMD, myPresto, and the like.

<Representative structure determination process>
In the representative structure determination step, one or more representative structures are determined based on a temporal change in the structure of the complex obtained by the first molecular dynamics calculation.
The complex is a complex of the target molecule and the drug candidate molecule.
The representative structure is a structure that represents a temporal change in the structure of the complex.

The specific method for determining the representative structure is not particularly limited and can be appropriately selected depending on the purpose. For example, the specific method may be appropriately selected according to the degree of time change of the structure of the composite. For example, when the structure of the complex has a large time change, similar structures may be selected and a representative structure may be determined from them. When the time change of the structure of the complex is small, the calculation time is divided at regular intervals, the time average of coordinates is obtained for each obtained time section, and the time average of coordinates is used as a representative structure. Is also good.
The method of determining the representative structure by the time average of the coordinates of the complex is preferable in that the programming is simple and the amount of calculation is small.

<Second MD calculation step>
In the second MD calculation step, a second molecular dynamics calculation is performed on the representative structure.
At the time of the second molecular dynamics calculation, the drug candidate molecule is restricted. Further, the partial structure of the target molecule is restricted. The partial structure is a partial structure at a position relatively distant from the drug candidate molecule in the target molecule. In other words, the partial structure is a first partial structure that is relatively farther from the drug candidate molecule than other partial structures among the plurality of partial structures included in the target molecule.
Here, the relatively distant position refers to, for example, a position distant to such an extent that there is no influence from the drug candidate molecule other than the interaction of charges.

  In the second MD calculation step, a partial structure near the drug candidate molecule in the target molecule is not restricted. In this case, examples of the partial structure include an amino acid residue. The vicinity is not particularly limited and may be appropriately selected depending on the intended purpose. For example, the vicinity may be within 6 nm from the drug candidate molecule, or the distance at which van der Waals interaction with the drug candidate molecule works. Good.

  When performing molecular dynamics calculation in the second MD calculation step, water molecules are arranged around the target molecule and the drug candidate molecule.

  The restriction of the drug candidate molecule may be performed on all atoms constituting the drug candidate molecule, or may be performed on all heavy atoms constituting the drug candidate molecule, or the drug candidate It may be carried out for one heavy atom constituting the molecule.

  The restriction of the partial structure may be performed on all atoms constituting the partial structure, may be performed on all heavy atoms constituting the partial structure, or may constitute the partial structure. It may be performed for one heavy atom.

  As a method of the constraint, for example, a method of applying a force to the atom to be bound so as to return to a specific coordinate when the atom moves, and the like can be mentioned.

  The second molecular dynamics calculation can be performed using a molecular dynamics calculation program. Examples of the molecular dynamics calculation program include AMBER, CHARMm, GROMACS, GROMOS, NAMD, myPresto, and the like.

  By the second MD calculation step, a local structural change of a complex formed by the target molecule and the drug candidate molecule (for example, a structural change of a binding site of the complex) can be analyzed.

<Water molecule extraction process>
In the water molecule extraction step, water molecules are extracted using the result of the second molecular dynamics calculation. In other words, the water molecule extraction step is a water molecule identification step of identifying a first water molecule of the plurality of water molecules using a result of the second molecular dynamics calculation.
It is preferable that the water molecule extraction step is performed based on at least one of the fluctuation width of the coordinates of the water molecule and the existence frequency of the water molecule. In other words, it is preferable that the water molecule identification step is performed based on at least one of the fluctuation width of the coordinates of the plurality of water molecules and the existence frequency of the plurality of water molecules.

The fluctuation width of the coordinates of the water molecule is obtained, for example, by analyzing the coordinates of the water molecule from the result of the second molecular dynamics calculation and evaluating the fluctuation width by root mean square fluctuation (RMSF). You can ask. Here, an equation for obtaining the RMSF is shown below.
Here, in the above equation, W (t) represents the coordinates of the water molecule at time t, W _REF represents the coordinates of the reference water molecule, and T represents the simulation time.
The water molecule having a small RMSF (W) continues to exist at coordinates at a short distance from both the target molecule and the drug candidate molecule, and thus has a large influence on the interaction between the target molecule and the drug candidate molecule.

  When extracting the water molecules based on the fluctuation width of the coordinates of the water molecules, a threshold may be provided to perform the extraction. Examples of the method of extracting water molecules based on the fluctuation width of the coordinates of the water molecules include a method of extracting water molecules having an RMSF of 2 ° or less. As the threshold value, a value predetermined as a default value in a computer may be used, or an arbitrary value may be set by a user.

  The presence frequency of the water molecule can be determined, for example, from the density distribution of the water molecule obtained by arranging all the water molecules in one space in the entire time of the second molecular dynamics calculation. Water molecules frequently exist at coordinates where the frequency of presence of water molecules is high. Water molecules existing at coordinates where the frequency of presence of water molecules is high, like water molecules having small fluctuations in coordinates, continue to be present at coordinates at short distances from both the target molecule and the drug candidate molecule. The effect on the interaction between the molecule and the drug candidate molecule is large.

  As a method of selecting coordinates having a high frequency of water molecules, for example, a method of selecting coordinates having a higher density (for example, a density of 10 times or more) than the density of an arbitrary low-density region in the density distribution of water molecules, and the like are available. No.

  By performing the second MD calculation step and the water molecule extraction step, the presence frequency of water molecules when the local fluctuation of the complex formed by the target molecule and the drug candidate molecule is taken into account Can be specified.

<Interaction energy calculation process>
In the interaction energy calculation step, the interaction energy between the target molecule and the drug candidate molecule is calculated in consideration of the extracted water molecule.

  The interaction energy calculation step is performed using, for example, the following processes A to D. The order of these processes does not matter.

<< Process A >>
In the process A, the pair interaction energy between the target molecule and the drug candidate molecule in the complex of the target molecule and the drug candidate molecule is calculated.

<< Processing B >>
In the process B, the polarization interaction energy of the target molecule in the complex with respect to the target molecule alone is calculated.

  The polarization interaction energy is the energy of polarization in the target molecule generated when the target molecule forms the complex with the drug candidate molecule from the state of the target molecule alone.

The polarization interaction energy can be determined, for example, by the following method.
The energy (E _P0 ) of the target molecule alone is calculated. At this time, a virtual water molecule is arranged around the target molecule. The virtual arrangement of water molecules can be performed by, for example, continuum approximation.
The energy (E _P1 ) of the target molecule in the complex is calculated. At this time, a virtual water molecule is arranged around the complex. The virtual arrangement of water molecules can be performed by, for example, continuum approximation.
Then, the polarization interaction energy is determined from the difference between the energy (E _P0 ) and the energy (E _P1 ).

<< Processing C >>
In the process C, the polarization interaction energy of the drug candidate molecule in the complex with respect to the drug candidate molecule alone is calculated.

  The polarization interaction energy is a polarization energy in the drug candidate molecule generated when the drug candidate molecule forms the complex with the target molecule from the state of the drug candidate molecule alone.

The polarization interaction energy can be determined, for example, by the following method.
The energy (E _L0 ) of the state in which the drug candidate molecule is a single substance is calculated. At this time, a virtual water molecule is arranged around the drug candidate molecule. The virtual arrangement of water molecules can be performed by, for example, continuum approximation.
The energy (E _L1 ) of the drug candidate molecule in the complex is calculated. At this time, a virtual water molecule is arranged around the complex. The virtual arrangement of water molecules can be performed by, for example, continuum approximation.
Then, the polarization interaction energy is determined from the difference between the energy (E _L0 ) and the energy (E _L1 ).

<< Process D >>
In the process D, a pair interaction energy between the extracted water molecule and the drug candidate molecule is calculated.

  In the processing D, it is preferable that the extracted water molecules are regarded as a part of the target molecules, in that the accuracy of the calculated interaction energy is improved.

  When considering the extracted water molecules, it is preferable to consider the water molecules as a part of the complex.

The interaction energy calculation step is obtained by, for example, quantum mechanics (QM) calculation. Examples of the quantum mechanical calculation include a molecular orbital calculation by a molecular orbital method. Examples of the molecular orbital calculation include ab initio molecular orbital calculation (ab initio molecular orbital calculation) and semi-empirical molecular orbital calculation.
Examples of the method of the ab initio molecular orbital calculation include a Hartree-Fock method and an electron correlation method.
The semi-empirical molecular orbital calculation methodology includes, for example, CNDO, INDO, AM1, PM3, and the like.
Examples of the program for the ab initio molecular orbital calculation include Gaussian 03, GAMESS, ABINIT-MP, and Protein DF.
The program for the semi-empirical molecular orbital calculation includes, for example, MOPAC.

  The method of calculating the interaction energy may be, for example, a general computer system including a CPU (Central Processing Unit), a RAM (Random Access Memory), a hard disk, various peripheral devices, and the like (eg, various network servers, workstations, personal computers). Etc.).

Subsequently, another example of the disclosed interaction energy calculation method will be described using a flowchart.
FIG. 2 is a flowchart for explaining a method of calculating the interaction energy.
[First MD calculation step]
First, the first MD calculation step is performed. In this step, a first molecular dynamics calculation is performed using a target molecule, a drug candidate molecule, and a plurality of water molecules around the target molecule and the drug candidate molecule.
Specifically, a molecular dynamics calculation in which the drug candidate molecule is restricted is performed.

(Representative structure determination step)
Next, the representative structure determination step is performed. In this step, based on the time change of the structure of the complex of the target molecule and the drug candidate molecule, which is obtained by the first molecular dynamics calculation, one or more representative of the time change of the structure of the complex Determine the representative structure.
Specifically, the structure included in the trajectory of the molecular dynamics calculation is classified for each structure in which the target molecule takes a similar position with respect to the position of the drug candidate molecule. Then, a representative structure in each of the classified structure groups is determined by a time average of coordinates.
Here, a plurality of representative structures are determined.

[Second MD calculation step]
Next, the second MD calculation step is performed. In this step, a second molecular dynamics calculation is performed on the representative structure while restricting the drug candidate molecule and restricting a partial structure of the target molecule relatively distant from the drug candidate molecule.
Specifically, while the drug candidate molecule is constrained, the influence from the drug candidate molecule is separated to such an extent that there is almost no interaction other than the charge interaction, and the representative structure in a state where the partial structure of the target molecule is also constrained. Perform molecular dynamics calculations on structures.

(Water molecule extraction step)
Next, a water molecule extraction step is performed. In this step, water molecules are extracted using the result of the second molecular dynamics calculation.
Specifically, extraction of water molecules is performed based on the frequency of presence of water molecules. The presence frequency of the water molecule is obtained by superimposing each snapshot over the entire time of the molecular dynamics calculation. When superimposing the snapshots, the coordinates at which the fluctuation of the coordinates of the constrained partial structure is minimized are set as the reference points for superimposition.

[Interaction Eg calculation step]
Next, the interaction energy calculation step (interaction Eg calculation step) is performed. In this step, the interaction energy between the target molecule and the drug candidate molecule is calculated in consideration of the extracted water molecule.
Specifically, the extracted water molecules are arranged at the extracted coordinates, and the interaction energy between the target molecule and the drug candidate molecule is calculated.

〔Recalculation〕
Next, in the plurality of representative structures determined in the representative structure determination step, there is a representative structure for which the second MD calculation step, the water molecule extraction step, and the interaction Eg calculation step have not been performed. For the representative structure, the second MD calculation step, the water molecule extraction step, and the interaction Eg calculation step are performed.
Then, recalculation is repeated for all the representative structures determined in the representative structure determination step until the interaction Eg calculation step ends.

[Determination of the most stable structure]
When the calculation of the interaction energies is completed for all the representative structures, all the calculated interaction energies are compared to determine the most stable interaction energy (binding free energy). The structure that takes the most stable interaction energy is defined as the most stable structure.

(program)
The disclosed program is a program that causes a computer to execute the disclosed interaction energy calculation method.
A preferred embodiment of the method for calculating the interaction energy is the same as a preferred embodiment of the method for calculating the interaction energy.

  The program can be created using various known programming languages according to the configuration of the computer system to be used and the type and version of the operating system.

The program may be recorded on a recording medium such as a built-in hard disk or an external hard disk, or may be stored in a compact disc read only memory (CD-ROM), a digital versatile disk read only memory (DVD-ROM), or an MO disc ( It may be recorded on a recording medium such as a magneto-optical disk or a USB memory [USB (Universal Serial Bus) flash drive]. When recording the program on a recording medium such as a CD-ROM, DVD-ROM, MO disk, or USB memory, if necessary, through a recording medium reading device of a computer system, directly or directly to a hard disk. Can be installed and used. In addition, the program is recorded in an external storage area (another computer or the like) accessible from the computer system through the information communication network, and, if necessary, directly or through the information storage network from the external storage area through the information communication network, or It can also be installed and used on a hard disk.
The program may be divided and recorded on a plurality of recording media for each arbitrary process.

(Computer readable recording medium)
The computer-readable recording medium of the disclosure records the above-described program of the disclosure.
The computer-readable recording medium is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include an internal hard disk, an external hard disk, a CD-ROM, a DVD-ROM, an MO disk, and a USB memory. Is mentioned.
The recording medium may be a plurality of recording media in which the program is divided and recorded for each process.

(Interaction energy calculation device)
The disclosed interaction energy calculation apparatus includes at least a first MD calculation unit, a representative structure determination unit, a second MD calculation unit, a water molecule extraction unit, and a calculation unit, and further includes other units as necessary. Is provided.
The first MD calculation unit performs a first molecular dynamics calculation using a target molecule, a drug candidate molecule, and a plurality of water molecules around the target molecule and the drug candidate molecule.
The representative structure determination unit represents a time change of the structure of the complex based on a time change of the structure of the complex of the target molecule and the drug candidate molecule, which is obtained by the first molecular dynamics calculation. One or more representative structures are determined.
The second MD calculation unit performs the second molecular dynamics calculation on the representative structure while constraining the drug candidate molecule and constraining a partial structure of the target molecule that is relatively far from the drug candidate molecule. Do.
The water molecule extraction unit extracts a water molecule using a result of the second molecular dynamics calculation. In other words, the water molecule extracting unit is a water molecule specifying unit that specifies a first water molecule of the plurality of water molecules by using a result of the second molecular dynamics calculation.
The calculation unit calculates an interaction energy between the target molecule and the drug candidate molecule in consideration of the extracted water molecule.

The preferred mode of the processing method of each unit in the interaction energy calculation device is the same as the preferred mode of each step in the interaction energy calculation method.
The calculation device may be a plurality of calculation devices each including a plurality of recording media on which the program is divided and recorded for each arbitrary process.

FIG. 3 shows a configuration example of the disclosed interaction energy calculation device.
The interaction energy calculation device 10 is configured by connecting a CPU 11, a memory 12, a storage unit 13, a display unit 14, an input unit 15, an output unit 16, an I / O interface unit 17, and the like via a system bus 18, for example. Is done.

  A CPU (Central Processing Unit) 11 performs operations (four arithmetic operations, comparison operations, and the like), and controls the operation of hardware and software.

  The memory 12 is a memory such as a RAM (Random Access Memory) and a ROM (Read Only Memory). The RAM stores an OS (Operating System) and application programs read from the ROM and the storage unit 13, and functions as a main memory and a work area of the CPU 11.

The storage unit 13 is a device that stores various programs and data, and is, for example, a hard disk. The storage unit 13 stores programs executed by the CPU 11, data necessary for executing the programs, an OS, and the like.
The program is stored in the storage unit 13, loaded into the RAM (main memory) of the memory 12, and executed by the CPU 11.

The display unit 14 is a display device, for example, a display device such as a CRT monitor and a liquid crystal panel.
The input unit 15 is an input device for various data, such as a keyboard and a pointing device (for example, a mouse).
The output unit 16 is an output device for various data, for example, a printer.
The I / O interface unit 17 is an interface for connecting various external devices. For example, input / output of data from a CD-ROM, a DVD-ROM, an MO disk, a USB memory, etc. is enabled.

FIG. 4 shows another configuration example of the disclosed interaction energy calculation device.
The configuration example of FIG. 4 is a cloud-type configuration example, in which the CPU 11 is independent of the storage unit 13 and the like. In this configuration example, a computer 30 storing the storage unit 13 and the like and a computer 40 storing the CPU 11 are connected via the network interface units 19 and 20.
The network interface units 19 and 20 are hardware for performing communication using the Internet.

FIG. 5 shows another configuration example of the disclosed interaction energy calculation device.
The configuration example in FIG. 5 is a cloud-type configuration example, and the storage unit 13 is independent of the CPU 11 and the like. In this configuration example, a computer 30 storing the CPU 11 and the like and a computer 40 storing the storage unit 13 are connected via the network interface units 19 and 20.

  Hereinafter, the disclosed technology will be described, but the disclosed technology is not limited to the following examples.

(Example 1)
The disclosed interaction energy calculation method was implemented according to the flow shown in FIG. Specifically, the operation was performed as follows. The step of calculating the interaction Eg is omitted.
Blood clotting factor Xa, which is a protein, was used as a target molecule.
RDR was used as a drug candidate molecule.
A molecular dynamics simulation using a crystal structure (1NFX) registered in a protein data bank (PDB) as an initial value was performed for 10 ns.
FIG. 6 is a diagram in which the simulation results, the RDR of 1NFX, the crystal structure of the water molecule of 1NFW, and the protein fXa are superimposed and displayed. The simulation result is obtained by superimposing 5,000 snapshots extracted every 1,000 points from 5 × 10 ⁶ snapshots obtained by calculation every 2 fs.
In FIG. 6, the protein fXa is omitted. In addition, since 1NFW captures water of crystallization better than 1NFX, the crystal structure of a 1NFW water molecule is used. In FIG. 6, “water molecule” indicates the crystal structure of a 1 NFW water molecule, and represents the position of an oxygen atom as a representative. Fine points around the RDR indicate the presence of water molecules obtained by simulation. These are the same in FIG.

(Comparative Example 1)
The crystal structure (1NFX) registered in the protein data bank (PDB) is changed in the same manner as in Example 1 except that the conventional method (MD calculation for freely moving only water molecules) described in the following document is used. A molecular dynamics simulation as an initial value was performed for 10 ns.
The results are shown in FIG. FIG. 7 is a diagram in which the RDR of 1NFX, the crystal structure of a water molecule of 1NFW, and the protein fXa are displayed in a superimposed manner with respect to the simulation result.
[Documents of conventional methods]
References: Abel R, Young T, Farid R, Berne BJ, and Friesner RA. The role of the active-site solvent in the thermodynamics of factor X alilig binding. J Am Chem Soc, 130: 2817-2831, 2008.

In Comparative Example 1, as shown in FIG. 7, the position of the water molecule confirmed in the crystal structure and the position where the distribution of the water molecule is concentrated in the simulation (the position that affects the interaction between the protein and the ligand) are shown. The concordance was poor, and only the portion corresponding to two of the six crystal waters could be estimated from the distribution of water molecules by simulation.
In contrast, in Example 1, as shown in FIG. 6, the positions of five out of six water molecules could be estimated by simulation.
From these results, it was confirmed that the disclosed technology can appropriately select a water molecule to be considered when calculating the interaction energy acting between the target molecule and the drug candidate molecule. Further, as a result of appropriately selecting the water molecules to be considered, it is not necessary to consider all the water molecules, so that the calculation time can be reduced.

Regarding the above embodiments, the following supplementary notes are further disclosed.
(Appendix 1)
Using a computer, the interaction energy between the target molecule and the drug candidate molecule is calculated, a method for calculating the interaction energy,
Performing a first molecular dynamics calculation using the target molecule, the drug candidate molecule, and a plurality of water molecules around the target molecule and the drug candidate molecule;
At least one representative structure representing the time change of the structure of the complex is determined based on the time change of the structure of the complex of the target molecule and the drug candidate molecule obtained by the first molecular dynamics calculation. The process of
Performing a second molecular dynamics calculation while constraining the drug candidate molecule for the representative structure, and constraining a partial structure relatively distant from the drug candidate molecule in the target molecule;
Extracting a water molecule using the result of the second molecular dynamics calculation;
In consideration of the extracted water molecules, the target molecule, the step of calculating the interaction energy of the drug candidate molecule,
A method for calculating interaction energy, comprising:
(Appendix 2)
2. The interaction energy calculation method according to claim 1, wherein the first molecular dynamics calculation is performed with the drug candidate molecule restricted.
(Appendix 3)
3. The method according to claim 1, wherein the representative structure is determined by a time average of coordinates of the complex.
(Appendix 4)
The method for calculating interaction energy according to any one of Supplementary notes 1 to 3, wherein the step of extracting the water molecule is performed based on at least one of a fluctuation width of the coordinates of the water molecule and an occurrence frequency of the water molecule. .
(Appendix 5)
On the computer,
Performing a first molecular dynamics calculation using a target molecule, a drug candidate molecule, and a plurality of water molecules around the target molecule and the drug candidate molecule;
At least one representative structure representing the time change of the structure of the complex is determined based on the time change of the structure of the complex of the target molecule and the drug candidate molecule obtained by the first molecular dynamics calculation. The process of
Performing a second molecular dynamics calculation while constraining the drug candidate molecule for the representative structure, and constraining a partial structure relatively distant from the drug candidate molecule in the target molecule;
Extracting a water molecule using the result of the second molecular dynamics calculation;
In consideration of the extracted water molecules, the target molecule, the step of calculating the interaction energy of the drug candidate molecule,
A program characterized by executing
(Appendix 6)
The program according to supplementary note 5, wherein the first molecular dynamics calculation is performed with the drug candidate molecule restricted.
(Appendix 7)
7. The program according to claim 5, wherein the representative structure is determined by a time average of coordinates of the complex.
(Appendix 8)
8. The program according to any one of supplementary notes 5 to 7, wherein the step of extracting the water molecules is performed based on at least one of a fluctuation width of the coordinates of the water molecules and an occurrence frequency of the water molecules.
(Appendix 9)
A first MD calculation unit that performs a first molecular dynamics calculation using a target molecule, a drug candidate molecule, and a plurality of water molecules around the target molecule and the drug candidate molecule;
At least one representative structure representing the time change of the structure of the complex is determined based on the time change of the structure of the complex of the target molecule and the drug candidate molecule obtained by the first molecular dynamics calculation. A representative structure determining unit,
A second MD calculation unit that performs a second molecular dynamics calculation while constraining the drug candidate molecule for the representative structure, and constraining a partial structure relatively far from the drug candidate molecule in the target molecule;
A water molecule extraction unit that extracts a water molecule using the result of the second molecular dynamics calculation;
In consideration of the extracted water molecules, the target molecule, a calculation unit that calculates the interaction energy of the drug candidate molecule,
An interaction energy calculation device, comprising:
(Appendix 10)
The apparatus for calculating an interaction energy according to claim 9, wherein the first molecular dynamics calculation is performed by restricting the drug candidate molecule.
(Appendix 11)
11. The interaction energy calculating device according to any one of supplementary notes 9 to 10, wherein the representative structure is determined by a time average of coordinates of the complex.
(Appendix 12)
The apparatus for calculating an interaction energy according to any one of Supplementary Notes 9 to 11, wherein the step of extracting the water molecule is performed based on at least one of a fluctuation width of coordinates of the water molecule and an occurrence frequency of the water molecule. .

10 Calculation device of interaction energy 11 CPU
12 memory 13 storage unit 14 display unit 15 input unit 16 output unit 17 I / O interface unit 18 system bus 19 network interface unit 20 network interface unit 30 computer 40 computer

Claims (9)

Using a computer, the interaction energy between the target molecule and the drug candidate molecule is calculated, a method for calculating the interaction energy,
Performing a first molecular dynamics calculation using the target molecule, the drug candidate molecule, and a plurality of water molecules around the target molecule and the drug candidate molecule;
At least one representative structure representing the time change of the structure of the complex is determined based on the time change of the structure of the complex of the target molecule and the drug candidate molecule obtained by the first molecular dynamics calculation. The process of
For the representative structure, while constraining the drug candidate molecule, and while constraining a first partial structure relatively far from the drug candidate molecule than other partial structures among the plurality of partial structures included in the target molecule, Performing a second molecular dynamics calculation;
Using the result of the second molecular dynamics calculation to identify a first water molecule of the plurality of water molecules ;
Taking into account the identified first water molecule, calculating the interaction energy between the target molecule and the drug candidate molecule;
Only including,
Calculating the interaction energy , wherein the step of specifying the first water molecule is performed based on at least one of a fluctuation width of coordinates of the plurality of water molecules and an existence frequency of the plurality of water molecules. Method.   The method according to claim 1, wherein the first molecular dynamics calculation is performed with the drug candidate molecule restricted.   The method for calculating interaction energy according to claim 1, wherein the representative structure is determined by a time average of coordinates of the complex. On the computer,
Performing a first molecular dynamics calculation using a target molecule, a drug candidate molecule, and a plurality of water molecules around the target molecule and the drug candidate molecule;
At least one representative structure representing the time change of the structure of the complex is determined based on the time change of the structure of the complex of the target molecule and the drug candidate molecule obtained by the first molecular dynamics calculation. The process of
For the representative structure, while constraining the drug candidate molecule, and while constraining a first partial structure relatively far from the drug candidate molecule than other partial structures among the plurality of partial structures included in the target molecule, Performing a second molecular dynamics calculation;
Using the result of the second molecular dynamics calculation to identify a first water molecule of the plurality of water molecules;
Taking into account the identified first water molecule, calculating the interaction energy between the target molecule and the drug candidate molecule;
And execute
A program, wherein the step of specifying the first water molecule is performed based on at least one of a fluctuation width of coordinates of the plurality of water molecules and an existence frequency of the plurality of water molecules. The program according to claim 4, wherein the first molecular dynamics calculation is performed while restricting the drug candidate molecule. The program according to claim 4, wherein the representative structure is determined by a time average of coordinates of the complex. A first MD calculation unit that performs a first molecular dynamics calculation using a target molecule, a drug candidate molecule, and a plurality of water molecules around the target molecule and the drug candidate molecule;
At least one representative structure representing the time change of the structure of the complex is determined based on the time change of the structure of the complex of the target molecule and the drug candidate molecule obtained by the first molecular dynamics calculation. A representative structure determining unit,
For the representative structure, while constraining the drug candidate molecule, and while constraining a first partial structure relatively far from the drug candidate molecule than other partial structures among the plurality of partial structures included in the target molecule, A second MD calculation unit for performing a second molecular dynamics calculation;
A water molecule identification unit that identifies a first water molecule of the plurality of water molecules using a result of the second molecular dynamics calculation;
In consideration of the identified first water molecule, the target molecule, a calculation unit that calculates the interaction energy between the drug candidate molecule,
With
The step of specifying the first water molecule in the water molecule specifying unit is performed based on at least one of a fluctuation width of coordinates of the plurality of water molecules and an occurrence frequency of the plurality of water molecules. Device for calculating the interaction energy. The apparatus for calculating an interaction energy according to claim 7, wherein the first molecular dynamics calculation is performed while restricting the drug candidate molecule. The interaction energy calculation device according to claim 7, wherein the representative structure is determined by a time average of coordinates of the complex.