WO2016072027A1 - Méthode de calcul de structure liée stable, dispositif de calcul, et programme - Google Patents

Méthode de calcul de structure liée stable, dispositif de calcul, et programme Download PDF

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Publication number
WO2016072027A1
WO2016072027A1 PCT/JP2014/079635 JP2014079635W WO2016072027A1 WO 2016072027 A1 WO2016072027 A1 WO 2016072027A1 JP 2014079635 W JP2014079635 W JP 2014079635W WO 2016072027 A1 WO2016072027 A1 WO 2016072027A1
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stable
drug candidate
molecule
candidate molecule
target molecule
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PCT/JP2014/079635
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English (en)
Japanese (ja)
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谷田　義明
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富士通株式会社
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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
    • G16B15/30—Drug targeting using structural data; Docking or binding prediction
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment

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  • This case relates to a method for calculating a stable binding structure between a target molecule and a drug candidate molecule, a calculation apparatus, and a program for executing the calculation method.
  • a drug candidate molecule is to calculate a molecule (ligand) that strongly interacts with a target molecule involved in a target disease (target disease) as a drug candidate. Therefore, screening of compounds based on the target molecule steric structure by computers is actively performed.
  • SBDD Structure-Based Drug Design
  • This method is a molecular design method based on the three-dimensional structure information of a target molecule (for example, protein).
  • the target molecule structure is fixed to one structure, and the drug candidate molecule has a shape within the binding site.
  • the design is aimed at achieving good agreement and minimizing energy.
  • the great advantage of drug discovery using a computer is that drug candidate molecule design and identification of a stable binding structure between a target molecule and a drug candidate molecule can be simultaneously obtained.
  • the stable binding structure between the target molecule and drug candidate molecule obtained by such a method has a large discrepancy from the actual stable binding structure, and the drug candidate molecule does not show the activity value as expected. There is.
  • an object of the present invention is to provide a calculation method and a calculation apparatus for a stable bond structure that can efficiently calculate a stable bond structure, and a program that executes the calculation method.
  • the method for calculating the disclosed stable bond structure is as follows: A method for calculating a stable binding structure of a target molecule and a drug candidate molecule using a computer, When searching for a second stable binding structure that is more stable than the first stable binding structure using metadynamics from the first stable binding structure of the target molecule and the drug candidate molecule, the first stability A plurality of states are prepared for the bond structure, and the second stable bond structure is searched.
  • the disclosed program is stored on a computer.
  • searching for a second stable binding structure that is more stable than the first stable binding structure using metadynamics from the first stable binding structure of the target molecule and drug candidate molecule the first stable binding structure A plurality of states are prepared for and the search for the second stable bond structure is executed.
  • the disclosed apparatus for calculating a stable binding structure searches for a second stable binding structure that is more stable than the first stable binding structure using metadynamics from the first stable binding structure of the target molecule and drug candidate molecule.
  • a search unit for preparing a plurality of states for the first stable coupling structure and searching for the second stable coupling structure is provided.
  • the conventional problems can be solved, the object can be achieved, and a stable bond structure can be calculated efficiently.
  • the disclosed program the conventional problems can be solved, the object can be achieved, and a stable coupling structure can be calculated efficiently.
  • the disclosed device for calculating a stable bond structure the conventional problems can be solved, the object can be achieved, and a stable bond structure can be calculated efficiently.
  • FIG. 1A is a conceptual diagram of a structure space search by simulated annealing (part 1).
  • FIG. 1B is a conceptual diagram of structural space search by simulated annealing (part 2).
  • FIG. 1C is a conceptual diagram of structural space search by simulated annealing (part 3).
  • FIG. 2A is a conceptual diagram of structure space search using metadynamics (part 1).
  • FIG. 2B is a conceptual diagram of a structure space search using metadynamics (part 2).
  • FIG. 2C is a conceptual diagram of structural space search using metadynamics (part 3).
  • FIG. 2D is a conceptual diagram of structural space search using metadynamics (part 4).
  • FIG. 3A is a conceptual diagram of a contour map of free energy (part 1).
  • FIG. 3A is a conceptual diagram of a contour map of free energy (part 1).
  • FIG. 3A is a conceptual diagram of a contour map of free energy (part 1).
  • FIG. 1A is a conceptual diagram of
  • FIG. 3B is a conceptual diagram of a contour map of free energy (part 2).
  • FIG. 4 is a flowchart of an example of the disclosed method for calculating a stable bond structure.
  • FIG. 5 is a flowchart of an example of an application example of the disclosed method for calculating a stable coupling structure.
  • FIG. 6 is a flowchart of another example of application of the disclosed method for calculating a stable coupling structure.
  • FIG. 7 is a hardware configuration example of the disclosed apparatus.
  • the disclosed method for calculating a stable binding structure is a method for calculating a stable binding structure of a target molecule and a drug candidate molecule using a computer.
  • the present inventor examined the search for a stable bond structure by simulated annealing.
  • the simulation temperature is set high and the search range is expanded to a structure space that cannot be searched by room temperature simulation. Thereafter, by gradually lowering the temperature (annealing: annealing), a more stable structure (stable bonding structure) can be found.
  • the first stable binding structure (binding pose A) between the target molecule and drug candidate molecule is determined by an arbitrary method (FIG. 1A).
  • the first stable bond structure (bonding pose A) is energetically more stable than the bond structure in the surrounding structure space.
  • the search range of the structure space is widened by setting the simulation temperature high (FIG. 1B).
  • a second stable coupling structure (coupling pose B) that is more stable than the first stable coupling structure (coupling pose A) can be found.
  • the simulated annealing has a problem.
  • the problem with this method is that the set temperature at a high temperature is as high as 500 ° C. to 1,000 ° C., and thus exceeds the denaturation temperature (about 60 ° C.) of the target molecule (for example, protein). Therefore, the target molecule does not return to a stable structure at room temperature after annealing.
  • a simulation using a classical potential is performed.
  • the present inventor next examined the search for a stable bond structure using metadynamics. Unlike the simulated annealing, the metadynamics attempts to widen the search range of the structure space by filling a potential valley with a penalty function. Therefore, in the metadynamics, the target molecule is not denatured and the water molecule network is not broken as in the simulated annealing. A Gaussian distribution is often used for the penalty function. However, in the metadynamics, which stable bond structure is found when escaping from a certain stable bond structure using the penalty function greatly depends on the speed direction of the drug candidate molecule at that time.
  • the present inventor prepared a plurality of states for the certain stable bond structure when searching for another stable bond structure using metadynamics from a certain stable bond structure, thereby efficiently creating a stable bond structure. I found that I could search.
  • Metadynamics is a method of tabu search. By placing a potential proportional to the existence probability on the coordinate axis (giving a penalty function), the existence probability in the area once visited is suppressed and smoothed on the coordinates. This is a technique for realizing a simple probability distribution.
  • the metadynamics is a method of smoothing the free energy surface by successively adding a small potential to the free energy curved surface (minimum) of the system by a penalty function. By using the metadynamics, it is possible to increase the probability of an event that normally occurs only rarely.
  • FIGS. 2A to 2D an example of adding a small potential to a free energy curved surface where a certain stable bond structure (bonding pose A) exists and searching for another stable bond structure (bonding pose B) is shown in FIGS. 2A to 2D.
  • the first stable binding structure (binding pose A) between the target molecule and drug candidate molecule is determined by an arbitrary method (FIG. 2A).
  • the first stable bond structure (bonding pose A) exists at the minimum of the free energy curved surface and is more energetically stable than the bond structure in the surrounding structure space.
  • a micropotential is given to the valley of the free energy curved surface where the first stable coupling structure (coupling pose A) exists (FIG. 2B). Then, the search range of the structure space is widened.
  • the first stable binding structure is a binding structure (binding pose) of the target molecule and the drug candidate molecule.
  • the method for determining the first stable binding structure is not particularly limited and may be appropriately selected depending on the purpose. For example, it may be determined by molecular dynamics simulation of the target molecule and the drug candidate molecule. However, it may be determined by flexible docking. In addition, the drug candidate molecule may be manually placed at the binding site of the target molecule in consideration of hydrogen bonding, van der Waals force and the like.
  • the first stable coupling structure preferably has a minimum energy value, but need not have a minimum energy value.
  • the molecular dynamics simulation can be performed using a molecular dynamics calculation program.
  • the molecular dynamics calculation program include AMBER, CHARMm, GROMACS, GROMOS, NAMD, myPresto, and the like.
  • the flexible docking can be performed using a docking program. Examples of the docking program include ICM, FlexE, ADAM, FlexX, AS dock, Ph4 dock, and the like.
  • the target molecule is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include protein, RNA (ribonucleic acid), DNA (deoxyribonucleic acid), and the like.
  • the determination of the first stable bond structure and the search for the second stable bond structure are preferably performed in a solvent, more preferably in water. By doing so, a stable bond structure closer to the bond structure in the living body can be obtained.
  • the search for the second stable binding structure using the metadynamics is performed with respect to the potential energy of the binding structure in the snapshot.
  • This can be done by applying a potential.
  • the penalty function is not particularly limited and can be appropriately selected according to the purpose, but is usually a Gaussian function.
  • the width and height of the penalty function parameters are not particularly limited and can be appropriately selected depending on the purpose.
  • the penalty function is usually given a plurality of times. There is no restriction
  • the penalty function may be given for each time step in the molecular dynamics simulation, or several time steps may be taken as one unit, and the penalty function may be given for each unit. Good. In that case, it is preferable that the parameter of the penalty function used is fixed.
  • the free energy landform includes, for example, a free energy valley in which a first stable coupling structure (coupling pose A) exists and a more stable second stable coupling structure (coupling pose B). There is a valley of free energy that exists.
  • each one of the arrows in the coupling pose A means one state of the first stable coupling structure (coupling pose A).
  • the relative positions of the first stable coupling structure (coupling pose A) and the second stable coupling structure (coupling pose B) are shown in the free energy contour maps. In free energy terrain, its relative position is unknown. Therefore, when searching for a more stable bond structure from the first stable bond structure (bonding pose A) using metadynamics, the state of the first stable bond structure (bonding pose A) is one. The second stable bond structure (bonding pose B) cannot be found or is very time consuming to find. On the other hand, when searching for a more stable bond structure from the first stable bond structure (bonding pose A) using metadynamics, by preparing a plurality of states of the first stable bond structure (bonding pose A) The second stable coupling structure (coupling pose B) can be found quickly.
  • seven states are prepared as the plurality of states.
  • the number is not particularly limited and can be appropriately selected according to calculation time, calculation accuracy, and the like. Examples of the number of the plurality of states include 2 to 60.
  • the plurality of states are preferably prepared by preparing a plurality of momentums of atoms of the drug candidate molecule in the first stable bond structure.
  • the momentum may be determined manually or by a random number.
  • the plurality of states may be prepared by changing the momentum of each atom constituting the drug candidate molecule by a random number. At that time, the coordinates of each atom in the plurality of states are the same.
  • the search for the second stable binding structure using the metadynamics is preferably performed by limiting the distance between the target molecule and the drug candidate molecule. By doing so, even if a plurality of states are prepared for the first stable coupling structure, the calculation amount does not become enormous.
  • the limitation on the distance between the target molecule and the drug candidate molecule is preferably the limitation on the distance between the binding site of the target molecule and the drug candidate molecule, and the limitation on retaining the drug candidate molecule in the binding site. More preferably. This is because a stable binding structure cannot be expected when the drug candidate molecule comes out of the binding site.
  • Examples of the restriction of retaining the drug candidate molecule in the binding site include, for example, the distance between the atom constituting the binding site of the target molecule and the atom constituting the drug candidate molecule from the atom constituting the binding site. Limiting the distance to the outer edge of the binding site or the vicinity of the outer edge of the outer edge may be mentioned. Here, if at least a part of the drug candidate molecule is present in the binding site, it corresponds to “retain the drug candidate molecule in the binding site”. Normally, in the first stable binding structure, the drug candidate molecule is located within the binding site of the target molecule.
  • the search for the second stable coupling structure using the metadynamics is preferably performed in a coordinate space including a distance and an angle, for example.
  • a distance (R1-L1) and angle (R1-L1-L2) are defined. Then, the distance (R1-L1) is set within a range slightly outside the binding site (for example, 0.5 mm).
  • a plurality of stable bond structures may be found when searching for the second stable bond structure from the first stable bond structure. Then, the most stable stable bond structure may be selected from the plurality of stable bond structures as the second stable bond structure.
  • the calculation method of the stable coupling structure is, for example, a normal computer system (for example, various network servers, workstations, personal computers) including a CPU (Central Processing Unit), a RAM (Random Access Memory), a hard disk, various peripheral devices, and the like. Etc.) can be realized.
  • a normal computer system for example, various network servers, workstations, personal computers
  • a CPU Central Processing Unit
  • RAM Random Access Memory
  • hard disk for example, various peripheral devices, and the like. Etc.
  • the disclosed program is a program that causes a computer to execute the disclosed calculation method of the stable bond structure.
  • a preferable aspect in the execution of the method for calculating the stable bond structure is the same as the preferable aspect in the method for calculating the stable bond structure.
  • the program can be created using various known programming languages according to the configuration of the computer system to be used and the type / version of the operating system.
  • the program may be recorded on a recording medium such as an internal hard disk or an external hard disk, a CD-ROM (Compact Disc Read Only Memory), a DVD-ROM (Digital Versatile Disk Read Only Memory), or an MO disk (You may record on recording media, such as a Magneto-Optical disk and USB memory [USB (Universal Serial Bus) flash drive].
  • a recording medium such as a CD-ROM, DVD-ROM, MO disk, USB memory, etc.
  • the program is directly stored on a hard disk or through a recording medium reader included in the computer system as needed. Can be installed and used.
  • the program is recorded in an external storage area (another computer or the like) that is accessible from the computer system through the information communication network, and if necessary, the program is directly stored in 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.
  • the disclosed computer-readable recording medium records the disclosed program.
  • the computer-readable recording medium is not particularly limited and can be appropriately selected according to the purpose.
  • an internal hard disk, an external hard disk, a CD-ROM, a DVD-ROM, an MO disk, a USB memory, etc. Is mentioned.
  • the recording medium may be a plurality of recording media on which the program is divided and recorded for each arbitrary process.
  • the disclosed stable coupling structure calculation apparatus includes at least a search unit, and further includes other units as necessary.
  • the search unit the first stable binding structure of the target molecule and drug candidate molecule is searched for a second stable binding structure that is more stable than the first stable binding structure using metadynamics.
  • a plurality of states are prepared for one stable bond structure, and the second stable bond structure is searched.
  • the plurality of states are preferably prepared by preparing a plurality of momentums of atoms of the drug candidate molecule in the first stable bond structure.
  • the search for the second stable binding structure using the metadynamics is preferably performed by limiting the distance between the target molecule and the drug candidate molecule.
  • the limitation on the distance between the target molecule and the drug candidate molecule is preferably a limitation on the distance between the binding site of the target molecule and the drug candidate molecule.
  • the limitation on the distance between the binding site of the target molecule and the drug candidate molecule is preferably a limitation that keeps the drug candidate molecule in the binding site.
  • 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.
  • the first stable binding structure of the target molecule and drug candidate molecule is determined. This determination is performed, for example, by placing drug candidate molecules in the target molecule binding site in consideration of hydrogen bonding and van der Waals forces. This is performed, for example, by manually inputting the coordinates of the target molecule and the drug candidate molecule into a computer.
  • a second stable bond structure that is more stable than the first stable bond structure is searched using metadynamics. At this time, a plurality of states are prepared for the first stable coupling structure. At this time, the distance between the target molecule and the drug candidate molecule is limited so that the drug candidate molecule remains in the binding site.
  • the first stable binding structure is variously changed, and the disclosed method for calculating the stable binding structure is used to bind the target molecule and the drug candidate molecule with a stable binding structure.
  • drug candidate molecules are designed or selected.
  • the drug candidate molecule can be designed, for example, by de novo design.
  • the drug candidate molecule can be selected, for example, by selecting from a compound library.
  • a first stable binding structure between the drug candidate molecule designed or selected and the target molecule is determined. The determination method can be performed according to the method described above.
  • a second stable bond structure that is more stable than the first stable bond structure is searched using metadynamics.
  • the search method can be performed according to the method described above. Next, it is determined whether or not to end the search.
  • the determination method is not particularly limited.
  • the first stable bond structure is determined based on conditions different from the previous conditions. That is, a first stable bond structure different from the first stable bond structure is determined.
  • a second stable bond structure that is more stable than the first stable bond structure is searched using metadynamics.
  • it is determined whether or not to end the search If the search is not terminated, a different first stable bond structure is further determined. When the search is terminated, the binding free energy is calculated for the second stable bond structure finally searched.
  • the binding free energy of the stable binding structure of the target molecule and the drug candidate molecule is calculated using the calculation method of the stable binding structure while changing the structure of the drug candidate molecule in various ways.
  • drug candidate molecules are designed or selected.
  • the drug candidate molecule can be designed, for example, by de novo design.
  • the drug candidate molecule can be selected, for example, by selecting from a compound library.
  • a first stable binding structure between the drug candidate molecule designed or selected and the target molecule is determined. The determination method can be performed according to the method described above.
  • a second stable bond structure that is more stable than the first stable bond structure is searched using metadynamics.
  • the search method can be performed according to the method described above. Next, it is determined whether or not to end the search. The determination method is not particularly limited. If the search is not terminated, drug candidate molecules are designed or selected again. This design or selection is the design or selection of a drug candidate molecule different from the previous drug candidate molecule. Next, a first stable binding structure between the drug candidate molecule designed or selected and the target molecule is determined. Next, using the first stable bond structure as a starting bond structure, a second stable bond structure that is more stable than the first stable bond structure is searched using metadynamics. Next, it is determined whether or not to end the search. If the search is not terminated, a different drug candidate molecule is further designed or selected. When the search is terminated, the binding free energy is calculated for the second stable bond structure finally searched.
  • FIG. 7 illustrates a hardware configuration example of the disclosed apparatus.
  • the apparatus 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.
  • a CPU (Central Processing Unit) 11 performs operations (four arithmetic operations, comparison operations, etc.), hardware and software operation control, and the like.
  • 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 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 a program executed by the CPU 11, data necessary for program execution, 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 or 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, and is, for example, a printer.
  • the I / O interface unit 17 is an interface for connecting various external devices. For example, input / output of data such as a CD-ROM, a DVD-ROM, an MO disk, and a USB memory is enabled.
  • RNA was used as a target molecule, and Theophylline was used as a drug candidate molecule.
  • the experimental value of the bond free energy of these bond structures (complexes) is ⁇ 8.92 kcal / mol.
  • the stable binding structure (binding pose) of the RNA and Theophylline was determined in consideration of hydrogen bond and van der Waals force.
  • the bond free energy of the obtained first stable bond structure (bonding pose A) is described in the literature [D. L. Mobley, J.M. D. Chodera, and K.C. A. Dill, J.M. Chem. Phys.
  • the second stable bond structure (bonding pose B) was searched using the molecular dynamics simulation package GROMACS using metadynamics. In the search, six states were prepared in the first stable coupling structure (coupling pose A). In this state, the momentum of atoms constituting Theophylline is determined by random numbers.
  • the bond free energy of the obtained second stable bond structure (bonding pose B) was determined by the alchemical conversion method with reference to the above-mentioned literature and found to be ⁇ 8.90 kcal / mol.

Abstract

La présente invention concerne une méthode d'utilisation d'un ordinateur pour calculer une structure liée stable comprenant une molécule cible et une molécule de médicament candidate, selon laquelle, lorsque l'on fait appel à la métadynamique pour rechercher une seconde structure liée stable plus stable qu'une première structure liée stable comprenant la molécule cible et la molécule de médicament candidate, on recherche la seconde structure liée stable par préparation d'une pluralité d'états de la première structure liée stable.
PCT/JP2014/079635 2014-11-07 2014-11-07 Méthode de calcul de structure liée stable, dispositif de calcul, et programme WO2016072027A1 (fr)

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WO2019130529A1 (fr) * 2017-12-28 2019-07-04 富士通株式会社 Procédé et dispositif permettant de calculer une structure de liaison stable et programme

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