WO2005103994A1 - リガンド分子の形状作成方法および装置 - Google Patents
リガンド分子の形状作成方法および装置 Download PDFInfo
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- WO2005103994A1 WO2005103994A1 PCT/JP2005/007595 JP2005007595W WO2005103994A1 WO 2005103994 A1 WO2005103994 A1 WO 2005103994A1 JP 2005007595 W JP2005007595 W JP 2005007595W WO 2005103994 A1 WO2005103994 A1 WO 2005103994A1
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
- G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
- G16C20/50—Molecular design, e.g. of drugs
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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
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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
Definitions
- the present invention relates to a method and an apparatus for creating a shape of a ligand molecule that binds to a biopolymer, for use in molecular design of a biologically active compound such as a medicine or an agricultural chemical.
- the ligand molecule In order for a ligand molecule such as a drug or a biologically active substance to exhibit a physiological activity, the ligand molecule is used as a target biological macromolecule (a pharmacological receptor, an enzyme, or a site for signal transduction between cells). (Including in-proteins and other proteins, nucleic acids and their complexes).
- a target biological macromolecule a pharmacological receptor, an enzyme, or a site for signal transduction between cells.
- the biopolymer and the ligand molecule In order to form a strong bond between the biopolymer and the ligand molecule in this way, the biopolymer and the ligand molecule must have complementary shapes, and furthermore, an affinity exists between the two molecules. is important. Among them, the shape of the ligand molecule is compared to the key of a key and a keyhole, and its importance is known.
- a ligand molecule for a certain biopolymer becomes clear, it is very useful for designing a chemical structure of a new compound or for screening a compound on a computer (so-called in-silico screening).
- drug discovery chemists can design compounds that fit well.
- drug discovery researchers will be able to design based on the comparison of ligand shapes of multiple biopolymers in order to obtain selectivity between biomolecules.
- a drug discovery scholar can perform screening using the shape of the ligand molecule.
- the shape of the ligand molecule is extremely useful particularly when designing a new drug or a bioactive substance based on the three-dimensional structure of a biopolymer.
- the shape of a ligand is determined by superimposing the ligand molecules on the basis of the structure of a plurality of ligand molecules.
- the obtained results differ depending on the conformation and the superposition method of the used ligand molecules, and the shape of the ligand cannot always be uniquely predicted.
- the ligand itself is not known, and cannot be applied to a biopolymer.
- Non-Patent Document 1 When searching for a ligand from the three-dimensional structure of a biopolymer, a method of simulating a stable binding state between the biopolymer and an arbitrary ligand molecule (a so-called docking study) is often performed (for example, , Non-Patent Document 1).
- the docking study is a method of searching for ligands that may have activity, and is not a method that can predict the shape of a ligand molecule.Therefore, the shape of a ligand is predicted only from the protein structure. You can't.
- Non-patent document 1 Yamada M. et al, J. Mol. Biol, 1994, Vol.243, p.310
- Non-Patent Document 2 Kuntz ID. Et al "J. Mol. Biol, 1982, Vol.161, p.269
- Non-Patent Document 3 Goodford P.J. et al., J. Med.Chem., 1985, Vol.28, p.849
- Non-Patent Document 4 Mattos C. et al "Nat. Biotech., 1996, Vol. 14, p. 595
- Non-Patent Document 5 Word J M. et al "J. Mol. Biol, 1999, Vol.285, p.1735
- Non-Patent Document 6 Per U n TJ, Propst C ⁇ al., Yoshiaki Kiso, Akiko translation Itai, "chemical and biological experimental line (44 Certificates) 'drug design computer-aided", Hirokawa Publishing Company, 1999, p. 289-295)
- the shape of a ligand is very useful information in a drug design (structure-based drug design) based on the three-dimensional structure of a biopolymer. No general method has been established to create the shape of the ligand molecule from the structure alone.
- An object of the present invention is to provide a method and an apparatus for forming a shape of a ligand molecule that binds to a biopolymer.
- Van der Waals force, Klonon force, and hydrogen bonding force are known as interaction forces acting between a biopolymer and a ligand molecule.
- Coulomb force is an interaction due to electric charge, and its value is greatly affected by the value of the point charge of the molecule and the dielectric constant of the solvent.
- Hydrogen bonding force is the force acting between electrically positive and negative atoms, and its value is directionally dependent and is also affected by the dielectric constant of the solvent.
- the van der Waals force is a force that works universally regardless of the polarity or non-polarity of the molecule, and is not affected by the dielectric constant of the surrounding solvent. Calculation is stable Give the result. Therefore, the present inventors focused on the use of the Van der Waals force, which is a universal interaction, and its potential.
- the present inventors have conducted intensive research on a method of creating a ligand shape based on only three-dimensional structural information of a biopolymer without using structural information of the ligand molecule. As a result, a virtual atom was placed in the ligand binding region of the biopolymer, and a method of calculating the van der Waals potential between the biopolymer and the virtual atom was considered.
- the method and apparatus of the present invention predict the shape of a ligand molecule that binds to a biopolymer based on only the information of the biopolymer without using the information of the ligand molecule, and calculate the shape of the ligand molecule.
- a three-dimensional space that is particularly important for binding to a biopolymer can be determined. Therefore, the present invention can be applied not only to biopolymers whose ligand molecules are known, but also to biopolymers whose ligand molecules are unknown.
- the method and apparatus of the present invention can create the shape of a ligand molecule using only van der Waals force without considering the interaction due to Coulomb force and hydrogen bonding, and Predict the shape of the ligand molecule without considering the solvent around the polymer and the type of biopolymer, etc., and determine the three-dimensional space that is particularly important for binding to the biopolymer among the shapes of the ligand molecule. Can be done.
- FIG. 1 is a flowchart for a first embodiment of the method of the present invention.
- FIG. 2 is a diagram showing a configuration of an apparatus used in the method of the present invention.
- FIG. 3 is a flowchart for a second embodiment of the method of the present invention.
- FIG. 4 is a schematic diagram showing the relationship between a biopolymer and the shape of a ligand molecule, a ligand binding site and a ligand binding region.
- FIG. 5 is a diagram showing a relationship between a biopolymer and a ligand binding region when the ligand binding region is designated as a rectangular parallelepiped.
- FIG. 6 is a view showing a predicted shape of a ligand molecule that binds to dihydrofolate reductase, obtained in Example 1.
- FIG. 7 is a diagram in which the shape of a ligand molecule obtained in Example 1 is superimposed on a known ligand molecule (methotrexate).
- FIG. 8 is a diagram obtained by superposing a three-dimensional space particularly important for binding of a ligand molecule and a known ligand molecule (methotrexate) obtained in Example 1.
- FIG. 9 is a view showing a predicted shape of a ligand molecule that binds to retinoic acid receptor gamma, obtained in Example 2.
- FIG. 10 is a diagram in which the predicted shape of a ligand molecule obtained in Example 2 is superimposed on a known ligand molecule (BMS 961).
- FIG. 11 is a view showing a predicted shape of a ligand molecule that binds to bacteriorhodopsin, obtained in Example 3.
- FIG. 12 is a diagram in which the predicted shape of a ligand molecule obtained in Example 3 is superimposed on a known ligand molecule (retinal).
- Biopolymer means a protein (eg, a receptor involved in signal transduction between cells, an enzyme, a cytokin), a nucleic acid, a complex thereof, and the like. Quality.
- ligand or "ligand molecule” means a low-molecular-weight compound (for example, an endogenous bioactive substance, a drug, a drug candidate or the like) that binds to a biopolymer.
- the “shape of a ligand molecule” means a steric space occupied by the ligand molecule when the ligand molecule and a biopolymer targeted by the molecule form a strong bond. That is, when a ligand molecule strongly binds to a biological macromolecule, it refers to a stereoscopic space occupied by the ligand molecule.
- the "ligand binding site” is a space where a biopolymer and a ligand bind. However, not all of that space is filled with ligand molecules (see Figure 4).
- Ligand binding region means a steric space of any shape including a ligand binding site.
- FIG. 2 is a diagram showing an example of the configuration of a computer device used in the method for forming a shape of a ligand molecule that binds to a biopolymer according to the present invention.
- the computer includes an input unit 100, a molecular data storage unit 210, a parameter storage unit 220, a virtual atom data storage unit 230, a Van der Waals potential calculation unit 310 (hereinafter, referred to as an E calculation unit), and a comparison unit 32 vdW.
- the input unit 100 includes a keyboard, a touch panel, a paper tape reader, a paper card reader, a disk (CD, DVD) reader, a magnetic tape reader, a floppy disk reader, and the like.
- Parameter holding unit 220, comparison unit 320, It is used for inputting data to the display figure creating unit 330 or the like.
- the molecular data holding unit 210 stores the types of atoms constituting the biopolymer described later and their coordinates.
- the molecular data holding unit 210 may be constituted by a main storage device of a computer or an external storage device (a readable / writable recording medium such as a node disk, CD, DVD, flash memory, magnetic tape, or floppy disk).
- the parameter holding unit 220 stores parameters for expressing atoms of a biopolymer and parameters for expressing virtual atoms, which will be described later.
- the parameter holding unit 220 may be constituted by a main storage device of the computer or an external storage device (a readable / writable recording medium such as a hard disk, a CD, a DVD, a flash memory, a magnetic tape, and a floppy disk).
- the virtual atom data holding unit 230 stores the three-dimensional coordinates of the three-dimensional lattice points generated in the ligand binding region described later, the van der Waals potential at each three-dimensional lattice point, and each three-dimensional lattice point. And a flag indicating that it has been removed.
- the virtual atomic data storage unit 230 is a main storage device of the computer! /, And may be constituted by an external storage device (hard disk, CD, DVD, flash memory, magnetic tape, floppy disk, or other readable / writable recording medium).
- the E operation unit 310 includes a CPU, a computer program stored in a storage medium, and a program vdW
- the computer-readable “storage medium” storing the computer program may be a hard disk, a CD, a DVD, a flash memory, a magnetic tape, a floppy disk, or the like.
- the working storage area is mainly composed of the main storage device of the computer, but a readable and writable recording medium such as a hard disk, a CD, a DVD, a flash memory, a magnetic tape, and a floppy disk may be used in combination.
- E The operation unit 310 converts the biopolymer stored in the molecular data holding unit 210 into vdW
- the types and coordinates of the constituent atoms, the parameters representing each atom of the biomolecule stored in the parameter storage unit 220 and the parameters representing virtual atoms, and the three-dimensional parameters stored in the virtual atom data storage unit 230 The three-dimensional coordinates of the lattice point are read out, and this information is applied to equation (I) to calculate the van der Waals potential of the three-dimensional lattice point. Then, the calculation result is associated with the coordinates of the three-dimensional lattice point, and the virtual atom data is Recorded in the data holding unit 230.
- the comparison unit 320 includes a CPU, a computer program stored in a storage medium, and a work storage area.
- a readable / writable recording medium such as a hard disk, a CD, a DVD, a flash memory, a magnetic tape, a floppy disk, etc. may be used in combination with a power mainly constituted by a main storage device of a computer.
- the comparison unit 320 compares the van der Waal potential of the three-dimensional lattice points stored in the virtual atom data holding unit 230 with a threshold value, and generates a flag indicating whether or not each three-dimensional lattice point should be removed. Recorded in the virtual atom data storage unit 230.
- the configuration may be such that the data of the three-dimensional lattice points to be removed is deleted from the virtual atom data holding unit 230.
- the threshold value may be read from the input unit 100.
- the display figure creating unit 330 is configured by a CPU, a computer program stored in a storage medium, and a work storage area.
- the work storage area is mainly composed of a main storage device of the computer, but a readable and writable recording medium such as a hard disk, a CD, a DVD, a flash memory, a magnetic tape, and a floppy disk may be used in combination.
- the display figure creating unit 330 creates a predicted shape of the ligand molecule using the three-dimensional coordinates of the three-dimensional lattice points stored in the virtual atom data holding unit 230, and displays the predicted shape on the display unit 400.
- the biopolymer may be configured to display the three-dimensional structure of the biopolymer together with the predicted shape of the ligand molecule using the three-dimensional coordinates of the atoms of the biopolymer held in the molecular data storage unit 210! . Further, R1 used when creating a predicted shape of the ligand molecule may be read from the input unit 100.
- the display unit 400 is well known in the art, such as a display, a printer, a plotter, and the like! It may consist of any visualization means.
- the device shown in FIG. 2 may be realized in a distributed computing environment.
- the input unit 100 may be configured as a communication interface to acquire various data via a network.
- the parameters expressing the atoms of the biopolymer are read out as the memory device power.
- the “storage device” in the present invention includes a reading device for a computer-readable recording medium such as a hard disk, a CD, a DVD, a flash memory, a magnetic tape, a floppy disk, and a buffer memory provided in the input unit 100 such as a keyboard. Also included.
- the parameters representing the biopolymer atoms may be determined by selecting a set of biopolymer atom descriptors, commonly known as force fields, or may be determined independently. .
- a force that selectively describes a CHARMm force field or an Amber force field as a parameter expressing an atom of a biological macromolecule is well known to those skilled in the art in place of these force fields. The same can be done using other force fields.
- the atomic parameters of the biopolymer read in this step are stored in the parameter holding unit 220 in FIG.
- v represents a virtual atom
- i represents the i-th atom of the biopolymer.
- R represents the distance between the center of the virtual atom and the center of the atom of the biopolymer.
- VR represents (The van der Waals radius (angstrom) of each atom.
- V ⁇ represents the van der Waals potential well depth (KcalZmol) of each atom.
- V ⁇ and VR of the virtual atom are defined.
- the parameters of the virtual atom can be defined with reference to the methyl group meter of the selected force field. Specifically, it is desirable that V ⁇ of the virtual atom be the same value as V ⁇ of the methyl group, and that the VR of the virtual atom be 85% to 100%, preferably 90 to 95% of the VR of the methyl group. Was found. Furthermore, the present inventors have made extensive studies and found that these values do not need to be changed regardless of the biopolymer.
- each VR may have a value different from that of the methyl group VR in a range of 85% to 100%.
- the parameters V ⁇ and VR of the virtual atom may be input from the input unit, or may be automatically generated from the parameters stored in the parameter holding unit 220 in the first step 10.
- the parameters V ⁇ and VR of the virtual atom defined in this step are also stored in the parameter holding unit 220.
- the parameters representing the atoms and virtual atoms of the biopolymer are converted to read-only media (CD-ROM, DVD-ROM, ROM, EPROM, EEPROM, etc.) by performing the first and second steps in advance. May be used as the parameter holding unit 220.
- the types of atoms constituting the biopolymer and their coordinates are read from the storage device.
- Information on atoms constituting a biopolymer can be input according to various methods well known to those skilled in the art. For example, a method for calculating the tertiary structural force obtained by X-ray crystallography or NMR analysis; a method for obtaining the protein structure using a protein crystal database, etc .; or a biopolymer model ( For example, a method of creating a homology modeling model) can be used. The information obtained according to these methods may not know the coordinates of the hydrogen atoms.
- the information of the coordinates of the hydrogen atom is added using known software, for example, Insight II (registered trademark), Reduce, or the like (for example, see Non-Patent Document 5).
- the subsequent steps may be performed by further inputting information on cofactors (eg, coenzymes, water molecules, metal ions, etc.) that play an important role by binding to the biopolymer.
- the reading in this step is performed by the input unit, and may be performed manually using a keyboard or the like, or may be information recorded in advance on a removable recording medium (floppy disk, CD, DVD, magnetic tape, etc.). May be performed by reading the information, or by downloading information via a communication line such as the Internet.
- the read data of the types and coordinates of the atoms constituting the biopolymer are stored in the molecular data holding unit 210.
- the fourth step 40 includes the following two sub-steps 41 and 42.
- a ligand binding region is specified.
- This ligand binding region can specify any part of the biopolymer. For example, it can be specified as any shape (sphere, cuboid, or any polyhedron) that includes the ligand binding site (see Figure 4).
- the ligand binding region is described as being specified as a rectangular parallelepiped.
- the method for specifying the ligand binding region is limited as long as the ligand binding region can be specified in relation to the atomic coordinate information of the biopolymer. There is no.
- the region encompassing the entire biopolymer input in the third step may be automatically designated by a computer, or information on the biopolymer (such as atomic species, interatomic bonds and coordinates) may be displayed on a display device. It may be displayed and the ligand binding region can be specified interactively.
- the designated ligand binding region is stored in the molecular data holding unit 210.
- a three-dimensional grid point is a point composed of three-dimensional coordinates generated at regular intervals.
- the three-dimensional coordinates for specifying a three-dimensional grid point can be based on any coordinate system such as a rectangular coordinate system (xyz), a polar coordinate system (r0 ⁇ ), or a cylindrical coordinate system (r ⁇ z). Although good, it is convenient to use coordinates based on a rectangular coordinate system.
- the interval between the three-dimensional lattice points is preferably 0.5 to 1.0 angstroms. It is.
- the generated three-dimensional coordinates of the plurality of three-dimensional lattice points are stored in the virtual atom data storage unit 230.
- the fifth step 50 virtual atoms are placed at one of the plurality of three-dimensional lattice points generated in the fourth step (substep 42), and the atoms of the biopolymer read out in the first step 10 are displayed.
- the van der Waals potential of the virtual atom is calculated.
- the calculated value is stored as a van der Waals potential at each three-dimensional lattice point.
- each three-dimensional lattice point is made to coincide with the center of a virtual atom.
- the E operation unit 310 includes a vdW that constitutes a biopolymer stored in the molecular data holding unit 210.
- the type and coordinates of each atom, the parameters (VR, V ⁇ ) representing each atom of the biopolymer stored in the parameter holding unit 220, the parameters (VR, V ⁇ ) representing virtual atoms, and the virtual atom data The three-dimensional coordinates of the three-dimensional lattice points stored in the holding unit 230 are read, and the information is applied to the equation (I) to calculate the van der Waals potential ⁇ of the three-dimensional lattice points. Then, the calculated ⁇ is defined as the coordinates of the three-dimensional grid point.
- the information is stored in the virtual atom data storage unit 230 in association with the data.
- a Van der Waals potential equal to or more than the first threshold E shown below is present.
- 3D lattice points to be removed By performing this step, the positions of the virtual atoms that are not stable, that is, the positions of the virtual atoms that are not desirable for bonding with the biopolymer can be removed.
- the present inventors have set E to be 7 to 11 times the absolute value of VE, more preferably 1 to 11 times the absolute value of V ⁇ . It has been found that it is preferable to set the number twice. This setting is effective when the atoms of the biopolymer are represented by the CHARMm force field or the Amber force field in the first step 10 and the parameters of the virtual atoms are within the range described in the second step 20.
- V ⁇ stored in the noramator holding section 220 is read out, and ⁇ is automatically generated.
- the comparing unit 320 sets the E and the three-dimensional lattice points set.
- a flag is displayed (recorded) on the data stored in the virtual atom data holding unit 230 to indicate whether the force satisfies the condition. It is convenient to show the data that has been removed. Alternatively, data satisfying the above condition may be deleted from the virtual atom data holding unit 230.
- the seventh step 70 includes the following two sub-steps 71 and 72.
- the display figure creating unit 330 generates a sphere having a radius R1 around each of the three-dimensional lattice points that have not been removed in the sixth step.
- R1 When determining the shape of a ligand molecule including hydrogen atoms, it is preferable to set R1 to 100 to 90% (preferably 100%) of VR when VR is within the range described in the second step.
- R1 is set to a VR force of 1.0 ⁇ to 0.9 ⁇ (preferably 0.9 ⁇ ). It is preferable to set a value obtained by subtracting 95 angstroms).
- the configuration may be such that VR is read from the meter storage unit 220 to automatically generate R1.
- the display figure creating unit 330 receives the input from the virtual atom data holding unit 230 and generates a spherical aggregate having the radius R1 as described above. [0054] (7-2)
- the display figure creating unit 330 makes the overlapping portion of the spherical aggregate generated in the sub-step 71 unique. That is, a hidden line processing is performed to obtain a three-dimensional contour of a spherical aggregate. The resulting three-dimensional space is the predicted result of the shape of the ligand molecule that binds to the biopolymer.
- the display unit 400 may be configured to display the three-dimensional structure of the biopolymer using the information of the biopolymer stored in the molecular data storage unit 210 together with the prediction result of the shape of the ligand molecule. .
- the input unit 100, the display figure creating unit 330, and the display unit 400 may be linked to display the prediction result and the shape of Z or biopolymer from the viewpoint specified by the operator.
- the first threshold value E used for the comparison in the sixth step is
- Data can be selected.
- the operator can also adjust the displayed E
- a suitable value may be input from the input unit 100. Then, using E selected or input by the operator, the sixth and seventh steps are performed again and
- the predicted shape of the gand molecule can be obtained.
- screening of candidate conjugates conforming to the shape can be performed. Specifically, by superimposing the three-dimensional structure of an arbitrary compound on the predicted ligand molecule shape and evaluating the fitness using various indexes (for example, shared volume, etc.), the compound becomes a candidate. It can be screened for suitability as a compound. Such superposition of the three-dimensional structures and evaluation of the degree of conformity can be performed using known software that can perform a three-dimensional search using the shape as a search condition.
- the catalyst when Catalyst (registered trademark) is used, the catalyst (registered trademark) is used as a search condition based on the shape of the ligand molecule as the prediction result.
- the three-dimensional search function of (Trademark) makes it possible to screen candidate conjugates.
- the shape of the ligand molecule obtained according to the method of the present invention is fitted with general chemical characteristics (for example, a hydrogen bonding region, a hydrophobic region, etc.) based on chemical considerations. It is also possible to evaluate the degree. By applying such screening to a group of library conjugates or a group of newly designed compounds, it becomes possible to efficiently screen candidate conjugates that bind to biopolymers.
- FIG. 3 shows a second embodiment of the present invention, in which, in addition to predicting the shape of a ligand molecule that binds to a biopolymer, a three-dimensional space that is particularly important for binding to a biopolymer is shown.
- 5 is a flowchart showing a method for determining the value. The method of the second embodiment can also be performed using the apparatus shown in FIG.
- the second embodiment of the present invention will be described in detail.
- the first to seventh steps of the above-described first embodiment are performed.
- the following steps are further performed to determine which region of the ligand molecule shape is particularly important for creating a strong bond. carry out.
- the original lattice points are further removed. Through this step, it is possible to determine a three-dimensional space that is particularly important for binding to a biopolymer.
- the atoms of the biopolymer are represented by the CH ARMm force field or the Amber force field. If the parameters of the virtual atoms are within the range described in the second step 20, E (E0) is expressed as ⁇ 12 times or less the absolute value of ⁇ , preferably — th2
- it is set to 14 times or more).
- This step is performed in the comparison unit 320, and the set E and th2
- a ninth step 90 is performed.
- the resulting spatial space is a three-dimensional space that is particularly important for the binding between the biopolymer and the ligand molecule.
- the three-dimensional space that is particularly important for binding to the obtained biopolymer can be displayed on the display unit 400.
- the display unit 400 may be configured to display the prediction result of the shape of the ligand molecule and the three-dimensional shape of the biopolymer held in the Z or molecular data holding unit 210.
- the predicted results of the three-dimensional space that are particularly important for binding to the biological macromolecule have different attributes (brightness, It is preferable that the display is performed with a change in saturation and hue, display with different hatching, blinking display, highlight display, and the like.
- the input unit 100, the display figure creating unit 330, and the display unit 400 cooperate with each other to predict the shape of the ligand molecule from the viewpoint specified by the operator.
- the three-dimensional space and the shape of Z or biopolymer which are particularly important for the user may be displayed.
- the method and apparatus of the present invention described above predict the shape of a ligand molecule that binds to a biopolymer based on only the information of the biopolymer without using the information of the ligand molecule. From the shape of the ligand molecule, a steric space that is particularly important for binding to a biopolymer can be determined. Therefore, the present invention can be applied not only to biopolymers whose ligand molecules are known, but also to biopolymers whose ligand molecules are unknown, and can be applied to biopolymers whose ligand molecules such as orphan receptors are unknown. By predicting the shape of the molecule, it is possible to determine, among the shapes of the ligand molecule, a three-dimensional space that is particularly important for binding to a biopolymer.
- the method and apparatus of the present invention create the shape of the ligand molecule using only Van der Waals forces, so that the solvent around the biopolymer, the type of biopolymer, and the like need not be considered. It is possible to predict the shape of the ligand molecule and to determine, among the shapes of Z or its ligand molecule, a steric space that is particularly important for binding to a biopolymer.
- the shape of the ligand molecule obtained by the method and apparatus of the present invention it is determined whether the library compound group or the newly designed compound group conforms to the shape of the ligand molecule.
- Silico screening it is possible to efficiently conduct a molecular design study of a drug active substance or a physiologically active substance.
- dihydrofolate reductase A specific example for carrying out the method of the present invention will be described using dihydrofolate reductase.
- Dihydrofolate reductase has been studied for a long time, and several X-ray crystal structures have been analyzed.
- the atomic coordinates of dihydrofolate reductase (DHFR) used the information of entry ID “1RX3” of Protein Data Bank. Also this As a descriptor of these atoms, a general CHARMm Version 22 (hereinafter, CHARMm) was used as a force field for a biopolymer.
- CHARMm a general CHARMm Version 22
- the van der Waals radius (VR) force of the methyl atom is 2.165 angstroms, and the depth (VE) of the potential well is defined as -0.11811 KcalZmol. Therefore, the virtual atom VR for calculating the Van der Waals potential is 1.95 ⁇ (about 90% of the methyl atom VR), and V £ is -0.1181 KcalZmol (100% of the methyl atom V ⁇ ). .
- a first threshold E of -1.8 KcalZmol (about -10 times the absolute value of V £ ) is set, and three-dimensional lattice points having a Van der Waals potential larger than E are removed.
- a sphere with a radius of Rl 1.0 angstroms (VR-0.95 angstroms) was generated, and the shape of the ligand molecule was created by making the overlapping portion unique.
- the shape of the obtained ligand molecule is shown in FIG.
- the methotrexate obtained from a known DHFR ′ methotrexate cocrystal (entry ID “1R X3” of the protein data bank) was used. Using three-dimensional coordinates, this methotrexate was superimposed with the shape of the ligand molecule obtained by the method of the present invention without moving the coordinates, and as shown in FIG. 7, it was confirmed that the methotrexate agreed very well. .
- a second threshold value E £ (about -14 times the absolute value) is set.
- FIG. 8 is a diagram in which the obtained three-dimensional space and methotrexate are similarly overlapped without moving the coordinates.
- the three-dimensional space determined in this way is consistent with the area occupied by the pyrimidine ring of methotrexate. From the results of X-ray crystallography, this pyrimidine ring part plays a large role in forming a stable DHFR-methotrexate complex by forming many hydrogen bonds and hydrophobic bonds with DHFR, and the activity of methotrexate It is known that the partial structure is indispensable (see Non-Patent Document 6).
- the three-dimensional space particularly important for binding to the biopolymer obtained by the method of the present invention using the second threshold value, and the pyrimidine which is a partial structure important for binding to DHFR in the molecular structure of methotrexate It was confirmed that the ring portion was well matched.
- RAR Retinoic acid receptor gamma
- CHARMm a general CHARMm Version22
- the virtual atom VR for calculating the Van der Waals potential is 1.95 angstroms (about 90% of the methyl atom VR), and ⁇ ⁇ is ⁇ 0.1181 KcalZmol (methyl atom V 100% of ⁇ ).
- the first threshold value E is set to 1.8 KcalZmol (about 10% of the absolute value of the virtual atom V E).
- a sphere with a radius of 1.0 angstroms (VR-0.95 angstroms) was generated at each of the three-dimensional lattice points that were removed, and the shape of the ligand molecule was created by making the overlapping portion unique.
- the shape of the obtained ligand molecule is shown in FIG.
- the van der Waals radius (VR) of a methyl atom is defined as 2.165 angstroms, and the depth (V ⁇ ) of a potential well is defined as 0.181 KcalZmol. Therefore, the virtual atom VR for calculating the van der Waals potential was 1.95 ⁇ (about 90% of the methyl atom VR), and ⁇ ⁇ was 0.181 KcalZmol (100% of the methyl atom V E).
- the first threshold E is set to 1.8 KcalZmol (about 10 times the absolute value of V £ )
- FIG. 11 shows the shape of the obtained ligand molecule.
- the shape of a ligand molecule that binds to a biopolymer can be created. Therefore, the method and apparatus of the present invention are extremely useful for molecular design of compounds having physiological activity such as medicines and agricultural chemicals.
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JP2013232126A (ja) * | 2012-04-27 | 2013-11-14 | Fujitsu Ltd | 計算支援プログラム、計算支援装置、および計算支援方法 |
WO2019078006A1 (ja) * | 2017-10-17 | 2019-04-25 | 富士フイルム株式会社 | 特徴量算出方法、特徴量算出プログラム、及び特徴量算出装置、スクリーニング方法、スクリーニングプログラム、及びスクリーニング装置、化合物創出方法、化合物創出プログラム、及び化合物創出装置 |
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WO1997018180A1 (fr) * | 1995-11-13 | 1997-05-22 | Akiko Itai | Procede de mise au point de compose physiologiquement actif |
WO1997024301A1 (fr) * | 1995-12-28 | 1997-07-10 | Akiko Itai | Procede de preparation d'un compose physiologiquement actif |
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JP3256307B2 (ja) * | 1993-01-07 | 2002-02-12 | 昭子 板井 | 生理活性を有するリガンドの分子構造を構築する方法 |
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WO1997018180A1 (fr) * | 1995-11-13 | 1997-05-22 | Akiko Itai | Procede de mise au point de compose physiologiquement actif |
WO1997024301A1 (fr) * | 1995-12-28 | 1997-07-10 | Akiko Itai | Procede de preparation d'un compose physiologiquement actif |
Non-Patent Citations (2)
Title |
---|
ITAI A. ET AL: "Lead Kagobutsu o Sosei suru", NIKKEI SCIENCE, vol. 24, no. 3, 1 March 1994 (1994-03-01), pages 42 - 45 * |
YAMAGUCHI Y. ET AL: "Bunshikan Sogo ni okeru Bunshi no Kyodo Kaiseki", DAI 29 KAI CHINO SYSTEM SYMPOSIUM SHIRYO, 2002, pages 271 - 276 * |
Cited By (3)
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JP2013232126A (ja) * | 2012-04-27 | 2013-11-14 | Fujitsu Ltd | 計算支援プログラム、計算支援装置、および計算支援方法 |
WO2019078006A1 (ja) * | 2017-10-17 | 2019-04-25 | 富士フイルム株式会社 | 特徴量算出方法、特徴量算出プログラム、及び特徴量算出装置、スクリーニング方法、スクリーニングプログラム、及びスクリーニング装置、化合物創出方法、化合物創出プログラム、及び化合物創出装置 |
JPWO2019078006A1 (ja) * | 2017-10-17 | 2020-09-10 | 富士フイルム株式会社 | 特徴量算出方法、特徴量算出プログラム、及び特徴量算出装置、スクリーニング方法、スクリーニングプログラム、及びスクリーニング装置、化合物創出方法、化合物創出プログラム、及び化合物創出装置 |
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