Methods, apparatus, devices, and computer readable storage media for virtual screening of coordination inhibitors

Abstract

The application provides a method, device, equipment and computer readable storage medium for virtually screening coordination inhibitors, which comprises: obtaining a plurality of candidate ligand molecules containing at least one coordination warhead in a coordination warhead set; performing molecular docking on the plurality of candidate ligand molecules and target proteins respectively to obtain a plurality of molecular conformations after docking; screening a first set of molecular conformations according to the distance between the coordination warhead in the plurality of molecular conformations and the coordination center of the target protein; obtaining the first binding free energy of the first set of molecular conformations after docking with the target protein according to a first binding free energy calculation method, and screening a second set of molecular conformations; screening a third set of molecular conformations from the second set of molecular conformations, wherein the target molecular conformations in the third set of molecular conformations satisfy the first preset condition of the second binding free energy and / or the second preset condition of coordination energy; and determining the coordination inhibitor according to the third set of molecular conformations. The application can improve the screening efficiency and success probability of the coordination inhibitor.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of active compound screening, and in particular to a method, device, equipment and computer readable storage medium for virtual screening of coordination inhibitors. BACKGROUND

[0002] New drug design and development is a creative and exploratory research work. Drug molecule design is to transform active compounds into safe, effective and controllable compounds in the human body through step-by-step optimization with rational strategy and scientific planning, to meet the requirements of multi-dimensional properties of drugs in the process of structure transformation and modification, and to construct new molecular entities with expected pharmacological activity. Among them, virtual screening is an important means in the process of lead compound discovery. Virtual screening (VS) is also called computer screening, which is based on small molecule database to carry out active compound screening. By using the molecular docking operation between small molecule compounds and drug targets, virtual screening can quickly select active compounds with drug properties from tens to millions of molecules, thereby greatly reducing the number of experimental screening compounds, shortening the research period and reducing the cost of drug research and development. However, in virtual screening, about 100 million molecules generate about 100 million conformations through molecular docking, which has the problem of low prediction accuracy, which is not conducive to screening potential active compounds. SUMMARY

[0003] The present application provides a method, device, equipment and computer readable storage medium for virtual screening of coordination inhibitors, which can improve the screening efficiency and success probability of coordination inhibitors. The method comprises:

[0004] Obtaining a plurality of candidate ligand molecules containing at least one coordination warhead in a coordination warhead set;

[0005] Molecularly docking the plurality of candidate ligand molecules with a target protein respectively, and obtaining a plurality of molecular conformations of the plurality of candidate ligand molecules after molecular docking with the target protein;

[0006] According to the distance between the coordination warhead in the plurality of molecular conformations and the coordination center of the target protein, a first molecular conformation set is screened from the plurality of molecular conformations;

[0007] According to a first binding free energy calculation method, a first binding free energy of each molecular conformation in the first molecular conformation set after docking with the target protein is obtained;

[0008] According to the first binding free energy, a second molecular conformation set is screened from the first molecular conformation set;

[0009] screening, from the second molecular conformation set, a target molecular conformation satisfying a first preset condition on a second binding free energy and / or a second preset condition on a coordination energy as a third molecular conformation set;

[0010] determining, according to the third molecular conformation set, a coordination inhibitor;

[0011] wherein the second binding free energy is a binding free energy of the target molecular conformation after docking with the target protein, calculated according to a second binding free energy calculation method;

[0012] wherein the coordination energy is a coordination energy of a coordination warhead of the target molecular conformation with a coordination center of the target protein, calculated according to a preset coordination energy calculation method.

[0013] Optionally, the screening, from the plurality of molecular conformations, a first molecular conformation set according to distances between coordination warheads of the plurality of molecular conformations and a coordination center of the target protein, comprises:

[0014] screening out, from the plurality of molecular conformations, a molecular conformation of a candidate ligand molecule whose coordination warhead has a distance less than a distance threshold to the coordination center of the target protein to form the first molecular conformation set.

[0015] Optionally, the second binding free energy calculation method has a higher calculation accuracy than the first binding free energy calculation method, and the first binding free energy calculation method has a higher calculation speed than the second binding free energy calculation method.

[0016] Optionally, the preset coordination energy calculation method is a quantum mechanics method.

[0017] Optionally, the calculation of the coordination energy of the coordination warhead of the target molecular conformation with the coordination center of the target protein according to the preset coordination energy calculation method comprises:

[0018] calculating the coordination energy of the coordination warhead of the target molecular conformation with the coordination center of the target protein according to the following formula:

[0019] Coordination energy = G (first complex) - G (first coordination center) - G (first coordination warhead);

[0020] wherein G (X) represents a free energy of X;

[0021] wherein when X is the first complex, it is a complex formed by the coordination warhead of the target molecular conformation and the coordination center of the target protein;

[0022] wherein when X is the first coordination warhead, it is the coordination warhead of the target molecular conformation;

[0023] wherein X is the first coordination center, is a coordination center of the target protein.

[0024] Optionally, the calculation of the coordination energy between the coordination warhead of the target molecule conformation and the coordination center of the target protein according to the preset coordination energy calculation method further comprises:

[0025] calculating G(X) according to H, T, S and G(X)=H-TS corresponding to the X;

[0026] wherein H=E+k B T, and

[0027]

[0028] wherein H is the enthalpy, T is the temperature, S is the entropy, k B is the Boltzmann constant, is the Hamiltonian operator, E is the total energy, respectively, are the kinetic energy operator, the potential energy operator, and the electron-electron interaction energy operator, h 2 is the reduced Planck constant, m i is the mass of particle i, r i is the position of particle i, and Ψ is the wave function of the system.

[0029] Optionally, the second binding free energy calculation method is the free energy perturbation method (FEP) or the thermodynamic integration method (TI).

[0030] Optionally, the screening of the target molecule conformation set from the second molecule conformation set to satisfy the first preset condition of the second binding free energy and / or the second preset condition of the coordination energy comprises:

[0031] screening a first candidate molecule conformation set from the second molecule conformation set to satisfy the first preset condition of the second binding free energy;

[0032] screening a target molecule conformation set from the first candidate molecule conformation set to satisfy the second preset condition of the coordination energy to form the third molecule conformation set.

[0033] Optionally, the screening of the target molecule conformation set from the second molecule conformation set to satisfy the first preset condition of the second binding free energy and / or the second preset condition of the coordination energy comprises:

[0034] screening a second candidate molecule conformation set from the second molecule conformation set to satisfy the second preset condition of the coordination energy;

[0035] Screening the second candidate molecular conformations from the second molecular conformation set to obtain a target molecular conformation set satisfying a first preset condition of second binding free energy, to form a third molecular conformation set.

[0036] Optionally, the screening the second candidate molecular conformations from the second molecular conformation set to obtain a target molecular conformation set satisfying a first preset condition of second binding free energy and / or a second preset condition of coordination energy, comprises:

[0037] Screening the first candidate molecular conformations from the second molecular conformation set to obtain a target molecular conformation set satisfying a first preset condition of second binding free energy, to form a first candidate molecular conformation set;

[0038] Screening the second candidate molecular conformations from the second molecular conformation set to obtain a target molecular conformation set satisfying a second preset condition of coordination energy, to form a second candidate molecular conformation set;

[0039] Determining the molecular conformations simultaneously located in the first candidate molecular conformation set and the second candidate molecular conformation set as target molecular conformations, to form a third molecular conformation set.

[0040] Optionally, the first binding free energy calculation method is to calculate the binding free energy according to the following function:

[0041] ΔG binding = ΔG0+ ΔG hbond Σ iI g1(Δr)g2(Δα)+ ΔG metal Σ aM f(r aM )+ ΔG lipo Σ lL f(r lL )

[0042] + ΔG rot H rot ; wherein,

[0043] ΔG0is obtained by multiple linear regression;

[0044] ΔG hbond Σ iI g1(Δr)g2(Δα) is a hydrogen bond term, Σ iI g1(Δr)g2(Δα) is used to calculate the complementarity of all hydrogen bonds between ligand atom i and receptor atom I, g1(Δr) is a function of hydrogen bond distance, and g2(Δα) is a function of hydrogen bond angle;

[0045] ΔG metal Σ aM f(r aM ) is a metal term, Σ aM f(r aM) for all acceptor and acceptor / donor atoms a in the ligand and any metal atom M in the acceptor, f(r aM ) is a function of the distance between the metal atom and the acceptor / donor atom in the ligand;

[0046] ΔG lipo Σ lL f(r lL ) is a hydrophobic term, Σ lL f(r lL ) for all lipophilic ligand atoms l and all lipophilic acceptor atoms L, f(r lL ) is a function of the distance between the hydrophobic atoms;

[0047] ΔG rot H rot is a frozen rotatable bond.

[0048] The apparatus for virtually screening coordination inhibitors comprises:

[0049] A collecting module is configured to acquire a plurality of candidate ligand molecules containing at least one coordination warhead in a coordination warhead set;

[0050] A first screening module is configured to perform molecular docking of the plurality of candidate ligand molecules with a target protein respectively, to acquire a plurality of molecular conformations of the plurality of candidate ligand molecules after the molecular docking with the target protein respectively, and to screen a first molecular conformation set from the plurality of molecular conformations according to a distance between a coordination warhead in the plurality of molecular conformations and a coordination center of the target protein;

[0051] A first acquiring module is configured to acquire, according to a first binding free energy calculation method, a first binding free energy of each molecular conformation in the first molecular conformation set after the molecular docking with the target protein;

[0052] A second screening module is configured to screen a second molecular conformation set from the first molecular conformation set according to the first binding free energy;

[0053] A third screening module is configured to screen a target molecular conformation set satisfying a first preset condition of a second binding free energy and / or a second preset condition of a coordination energy from the second molecular conformation set to form a third molecular conformation set;

[0054] A determining module is configured to determine a coordination inhibitor according to the third molecular conformation set;

[0055] The second binding free energy is a binding free energy of the target molecular conformation after the molecular docking with the target protein, which is calculated according to a second binding free energy calculation method;

[0056] The coordination energy is calculated according to a preset coordination energy calculation method.

[0057] The device for virtually screening the coordination inhibitor comprises a memory and a processor, and the memory stores executable code.

[0058] The computer readable storage medium stores executable code.

[0059] The method provided by the present application can realize rapid screening of coordination inhibitors from millions of molecules, and can improve the accuracy of the candidate coordination inhibitors and the target protein can have a real coordination inhibition effect, that is, improve the efficiency and success probability of screening the coordination inhibitors active to the target protein. BRIEF DESCRIPTION OF DRAWINGS

[0060] Figure 1 is a schematic diagram of one embodiment of the method for virtually screening the coordination inhibitor of the present application;

[0061] Figure 2 is a schematic diagram of one embodiment of the device for virtually screening the coordination inhibitor in the present application;

[0062] Figure 3 is a schematic diagram of one embodiment of the device for virtually screening the coordination inhibitor in the present application. DETAILED DESCRIPTION

[0063] Embodiments of the present application will be described in more detail by making reference to the drawings. Although the embodiments of the present application are shown in the drawings, it should be understood that the present application can be implemented in various forms and should not be limited by the embodiments described herein. On the contrary, these embodiments are provided to make the present application more thorough and complete, and to fully convey the scope of the present application to those skilled in the art.

[0064] The terms used in the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a", "an" and "the" used in the present application and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise. It should also be understood that the term "and / or" used herein means and includes any or all possible combinations of one or more associated listed items.

[0065] It should be understood that, although the terms "first", "second", "third", etc. can be used herein to describe various information, the information should not be limited to these terms. These terms are only used to distinguish one type of information from another type of information. For example, without departing from the scope of the present application, first information can also be referred to as second information, and similarly, second information can also be referred to as first information. Therefore, the features defined as "first", "second" can explicitly or implicitly include one or more of the features. In the description of the present application, the meaning of "a plurality of" is two or more, unless otherwise specifically limited.

[0066] As shown in Figure 1 , Figure 1 is a schematic diagram of one embodiment of the method of the present application for virtually screening coordination inhibitors. The method comprises:

[0067] Step S101, obtaining a plurality of candidate ligand molecules containing at least one coordination warhead in a coordination warhead set.

[0068] There are various methods for collecting the coordination warhead set. For example, all potential coordination warheads that can be used as coordination warheads in coordination inhibitors can be added to the coordination warhead set by collecting coordination warheads of coordination inhibitors mentioned in public materials. Alternatively, the plurality of candidate ligand molecules can be screened from ligand molecules in a molecular library. The molecular library can be a small molecule database, such as known databases such as ZINC, Specs, ChemBridge, etc., without limitation. The ligand molecules containing the collected coordination warheads are screened from the molecular library as candidate ligand molecules.

[0069] Step S102, respectively docking the plurality of candidate ligand molecules with a target protein to obtain a plurality of molecular conformations of the plurality of candidate ligand molecules after docking with the target protein.

[0070] Alternatively, the target protein is subjected to target protein hydrogenation treatment and target protein energy minimization treatment. The method of docking the candidate ligand molecules with the target protein can be a conventional docking method. After docking each candidate ligand molecule with the target protein, at least one molecular conformation is obtained, for example, a plurality of molecular conformations are obtained. All molecular conformations obtained after docking all candidate ligand molecules with the target protein are used as the object of initial screening.

[0071] Step S103, screening a first molecular conformation set from the plurality of molecular conformations according to the distance between the coordination warhead in the plurality of molecular conformations and the coordination center of the target protein.

[0072] The coordination center of the target protein refers to a center atom or ion that is completely or partially combined with a ligand through a coordination bond in the target protein. Alternatively, the molecular conformations in which the coordination warhead has a distance to the coordination center of the target protein less than a distance threshold are screened out to form the first set of molecular conformations. The distance less than the distance threshold indicates that the molecular conformation has the potential for coordination. The distance threshold can be determined according to the actual coordination distance of the coordination bond in the co-crystal structure formed by the known coordination inhibitor and the target protein, for example, any value from 1.7 angstroms to 3.2 angstroms, such as 1.8, 2, 2.1, 2.2, 2.5, 2.7, 3 angstroms, and the like.

[0073] In step S104, the first binding free energy of each molecular conformation in the first set of molecular conformations after docking with the target protein is obtained according to the first binding free energy calculation method.

[0074] Alternatively, the first binding free energy calculation method uses the following function to calculate the first binding free energy of each molecular conformation in the first set of molecular conformations after docking with the target protein:

[0075] ΔG binding = ΔG0+ ΔG hbond Σ iI g1(Δr)g2(Δα)+ ΔG metal Σ aM f(r aM )+ ΔG lipo Σ lL f(r lL )

[0076] + ΔG rot H rot ; wherein ΔG binding is the binding free energy, ΔG0may be obtained by multiple linear regression; ΔG hbond Σ iI g1(Δr)g2(Δα) is a hydrogen bond term, Σ iI g1(Δr)g2(Δα) is used to calculate the complementarity of all hydrogen bonds between ligand atom i and acceptor atom I, g1(Δr) is a function of the hydrogen bond distance, and g2(Δα) is a function of the hydrogen bond angle; ΔG metal Σ aM f(r aM ) is a metal term, Σ aM f(r aM ) is used to calculate all acceptors and acceptor / donor atoms a in the ligand molecule and any metal atoms M in the acceptor, and f(r aM ) is a function of the distance between the metal atom and the acceptor / donor atom in the ligand; ΔG lipo Σ lL f(rlL ) is a hydrophobic term,∑ lL f(r lL ) is used to calculate all lipophilic ligand atoms l and all lipophilic receptor atoms L, f(r lL ) is a function of the distance between hydrophobic atoms; ΔG rot H rot is a frozen rotatable bond.

[0077] Optionally, the first binding free energy calculation method can also be other existing scoring function methods of binding free energy.

[0078] Step S105, filtering out a second set of molecular conformations from the first set of molecular conformations according to the first binding free energy.

[0079] There are various methods for filtering out the second set of molecular conformations. Optionally, after obtaining the first binding free energy of each molecular conformation in the first set of molecular conformations after docking with the target protein by using the first binding free energy calculation method, the molecular conformation corresponding to the first binding free energy within a first preset range is filtered out as the second set of molecular conformations; or, all the calculated first binding free energies are sorted according to the numerical values, and the molecular conformation corresponding to the first binding free energy within a first preset proportion is filtered out as the second set of molecular conformations. For example, the molecular conformation within a certain proportion in the sorting from small to large is filtered out as the second set of molecular conformations, and the certain proportion can be any positive value. The numerical value of the calculated binding free energy is generally negative, and the smaller the numerical value of the binding free energy, i.e., the larger the absolute value of the numerical value, the stronger the binding ability of the ligand molecule to the target protein.

[0080] Step S106, filtering out a third set of molecular conformations from the second set of molecular conformations, wherein the target molecular conformations whose second binding free energy satisfies a first preset condition and / or coordination energy satisfies a second preset condition.

[0081] For the molecular conformations in the second set of molecular conformations for which the second binding free energy is to be calculated, the second binding free energy of the molecular conformation is the binding free energy after docking with the target protein, which is calculated according to the second binding free energy calculation method. Optionally, the calculation accuracy of the second binding free energy calculation method is higher than that of the first binding free energy calculation method, and the calculation speed of the first binding free energy calculation method is higher than that of the second binding free energy calculation method. The molecular conformations in the second set of molecular conformations for which the second binding free energy is to be calculated can be all the molecular conformations in the second set of molecular conformations.

[0082] For the molecule conformation in the second molecule conformation set whose coordination energy is to be calculated, the coordination energy of the molecule conformation is the coordination energy between the coordination head of the molecule conformation and the coordination center of the target protein calculated according to the preset coordination energy calculation method. The molecule conformation in the second molecule conformation set whose coordination energy is to be calculated can be all the molecule conformations in the second molecule conformation set.

[0083] In the example in which the third molecule conformation set is screened according to the second binding free energy and the coordination energy, optionally, in the first example, the first candidate molecule conformation set is composed of the first candidate molecule conformations in the second molecule conformation set whose second binding free energy satisfies the first preset condition; the second candidate molecule conformation set is composed of the second candidate molecule conformations in the second molecule conformation set whose coordination energy satisfies the second preset condition; the molecule conformation simultaneously located in the first candidate molecule conformation set and the second candidate molecule conformation set is determined as the target molecule conformation to form the third molecule conformation set.

[0084] Alternatively, in the second example, the first candidate molecule conformation set is composed of the first candidate molecule conformations in the second molecule conformation set whose second binding free energy satisfies the first preset condition; then the target molecule conformation set is composed of the target molecule conformations in the first candidate molecule conformation set whose coordination energy satisfies the second preset condition. In this example, the molecule conformation whose second binding free energy is to be calculated is all the molecule conformations in the second molecule conformation set, and the molecule conformation whose coordination energy is to be calculated is all the molecule conformations in the first candidate molecule conformation set.

[0085] Alternatively, in the third example, the second candidate molecule conformation set is composed of the second candidate molecule conformations in the second molecule conformation set whose coordination energy satisfies the second preset condition; then the target molecule conformation set is composed of the target molecule conformations in the second candidate molecule conformation set whose second binding free energy satisfies the first preset condition. In this example, the molecule conformation whose coordination energy is to be calculated is all the molecule conformations in the second molecule conformation set, and the molecule conformation whose second binding free energy is to be calculated is all the molecule conformations in the second candidate molecule conformation set.

[0086] The second and third examples described above can reduce the calculation amount and improve the calculation efficiency compared with the first example, and the second example is preferred because the calculation efficiency of the coordination energy is lower than that of the binding free energy, and the second example can take into account the efficiency and cost.

[0087] The method for screening the molecular conformation whose second binding free energy meets the first preset condition is various. Alternatively, for the screening objects (e.g., all the molecular conformations in the second molecular conformation set, or all the second candidate molecular conformations described above) to be screened according to the second binding free energy, after the second binding free energy of each molecular conformation in the screening objects and the target protein is obtained, the molecular conformation corresponding to the second binding free energy within the first preset range is screened out as the molecular conformation whose second binding free energy meets the first preset condition; or all the calculated second binding free energies are sorted according to the numerical value, and the molecular conformation corresponding to the second binding free energy within the first preset proportion range is screened out as the molecular conformation whose second binding free energy meets the first preset condition. For example, the molecular conformation within a certain proportion in the sorting from small to large is screened out as the second molecular conformation set, and the certain proportion can be any positive value.

[0088] Alternatively, if the number of molecular conformations corresponding to the same candidate ligand molecule in the molecular conformations whose second binding free energy meets the first preset condition exceeds a certain upper limit in the screening, the molecular conformations corresponding to the same candidate ligand molecule can be filtered out from the screening objects, and then the molecular conformations whose second binding free energy meets the first preset condition are screened out from the remaining molecular conformations in the screening objects. When the molecular conformations corresponding to the same candidate ligand molecule are filtered out, the number of the filtered molecular conformations can be determined according to a predetermined proportion or a preset number.

[0089] The method for screening the molecular conformation whose coordination energy meets the second preset condition is various. Alternatively, for the screening objects (e.g., all the molecular conformations in the second molecular conformation set, or all the first candidate molecular conformations described above) to be screened according to the coordination energy, after the coordination energy of each screening object is obtained, the molecular conformation corresponding to the coordination energy within the second preset range is screened out as the molecular conformation whose coordination energy meets the second preset condition; or all the calculated coordination energies are sorted according to the numerical value, and the molecular conformation corresponding to the coordination energy within the second preset proportion range is screened out as the molecular conformation whose coordination energy meets the second preset condition. For example, the molecular conformation within a certain proportion in the sorting from large to small is screened out, and the certain proportion can be any positive value. The calculated coordination energy is generally negative, and the smaller the numerical value, the larger the absolute value of the numerical value, which means that the binding ability of the coordination warhead in the candidate ligand molecule and the coordination center of the target protein is stronger.

[0090] Optionally, when the number of molecular conformations corresponding to the same candidate ligand molecule in the molecular conformations satisfying the second preset condition in the screening exceeds a certain upper limit, the part of the molecular conformations corresponding to the same candidate ligand molecule are filtered out from the screening objects, and then the molecular conformations satisfying the second preset condition are screened from the remaining molecular conformations in the screening objects. When the part of the molecular conformations corresponding to the same candidate ligand molecule are filtered out, the number of the filtered-out molecular conformations can be determined according to a predetermined ratio or a preset number, for example, only the molecular conformation with the minimum coordination energy is retained.

[0091] In step S107, the coordination inhibitor is determined according to the third set of molecular conformations.

[0092] Optionally, the candidate ligand molecule corresponding to the molecular conformation in the third set of molecular conformations is directly used as the coordination inhibitor, or the third set of molecular conformations can be further screened, and the candidate ligand molecule corresponding to the screened molecular conformation is used as the coordination inhibitor.

[0093] In the method for virtually screening the coordination inhibitor according to the embodiments of the present application, first, a plurality of candidate ligand molecules containing coordination warheads are filtered out based on the structure, and then a plurality of molecular conformations are obtained by docking the candidate ligand molecules with the target protein. The first binding free energy of each molecular conformation with the target protein is used for the first screening to filter out part of the molecular conformations. Then, the screened molecular conformations are screened again based on the second binding free energy and / or the coordination energy to screen out the molecular conformation set with better binding capacity as the candidate molecular conformation set, and then the corresponding candidate molecule (i.e., the coordination inhibitor) is determined according to the candidate molecular conformation. Such a screening process can ensure the rapid prediction of the binding free energy of the molecular conformation while improving the accuracy of the candidate coordination inhibitor that can have a real coordination inhibition effect on the target protein, i.e., improving the efficiency and success probability of screening the coordination inhibitor with activity on the target protein.

[0094] Moreover, in the example of using the coordination energy to screen the third set of molecular conformations, compared with the quantum mechanical method / molecular mechanical method used in the prior art to calculate the binding energy of the entire target protein and the candidate ligand molecule (i.e., the possible coordination inhibitor), the calculation amount is large, the efficiency is low, and the cost is high. In the present application, only the energy of the coordination warhead of the candidate ligand molecule and the coordination center of the target protein is calculated by quantum mechanics, which can greatly reduce the calculation amount, improve the efficiency, and reduce the cost.

[0095] In addition, compared with the docking method based on quantum mechanics in the prior art and the docking method in which the range of interaction between the metal and the ligand warhead is specified, the step S103 in the embodiment of the present application uses a common docking method, and the potential possible coordination inhibitors are screened out by distance restriction, and then the first binding free energy is calculated, and optionally, the second binding free energy is used to screen out the third set of molecular conformations, which is relatively smaller in calculation amount, lower in cost, and higher in efficiency.

[0096] Optionally, in the step S106, the second binding free energy calculation method can be the same as or different from the first binding free energy calculation method. For example, the second binding free energy calculation method can be to calculate by using a preset binding free energy calculation function or by using other existing binding free energy scoring functions. Optionally, the second binding free energy calculation method can be a free energy calculation method with higher accuracy than the first binding free energy calculation method. By using a free energy calculation method with lower accuracy to obtain the first binding free energy for one screening and then using a free energy calculation method with higher accuracy to obtain the second binding free energy for another screening, since the number of molecular conformations used to calculate the second binding free energy has been greatly reduced after multiple screenings, the screening of the molecular conformations can take into account both the efficiency and the success rate.

[0097] Optionally, the second binding free energy is obtained based on a free energy perturbation (FEP) method or a thermodynamic integration (TI) method. The FEP method and the TI method are both free energy calculation methods with higher accuracy based on molecular force fields, and are both high-precision methods for evaluating the binding strength of a drug small molecule and a target protein. The two methods are mainly based on the principle of a thermodynamic cycle, and can calculate the binding free energy of a ligand molecule by a series of gradual changes in van der Waals parameters and charge parameters at the atomic level.

[0098] Wherein, when the FEP method is used to obtain the second binding free energy, the complete, unmutated target protein (receptor) and a single molecular conformation form a complex, and the binding free energy from the binding state A to the binding state B of the complex is calculated by the Zwanzig equation (i.e., the formula below), and the second binding free energy is calculated according to the calculated ΔF(A→B).

[0099]

[0100] Wherein, the binding state A is the binding state of the reference ligand molecule A and the target protein, or the stable state of the water molecule and the target protein, or no binding state A (F A=0); the bound state B is the binding state of the candidate ligand molecule B with the target protein, T is the temperature, kJ / m³. B It is Boltzmann's constant, indicated by the triangle brackets. The term in F represents the average value of the simulation run of the associative state A. B F represents the Helmholtz free energy of the binding of candidate ligand molecule B to the target protein. A It refers to the Helmholtz free energy of the reference ligand molecule A binding to the target protein or the Helmholtz free energy of the water molecule binding to the target protein. ΔF represents the binding free energy of bound state B (the Helmholtz free energy of candidate ligand molecule B binding to the target protein) and the binding free energy of bound state A (the Helmholtz free energy of the reference ligand molecule A binding to the target protein, the Helmholtz free energy of the water molecule binding to the target protein, or F when there is no bound state A). A The difference in free energy.

[0101] The reference ligand molecule A can be a small molecule compound whose co-crystal structure with the target protein is known and whose molecular conformation of the reference ligand molecule in the co-crystal structure is resolved. It can also be a known marketed small molecule drug, a candidate small molecule compound in the research and development pipeline, or a reported active small molecule compound.

[0102] In obtaining the second binding free energy using the TI method, the difference in free energy is calculated by defining the thermodynamic path between states and integrating the ensemble-average enthalpy change along the path. Therefore, the second binding free energy obtained using the TI method can be calculated using the following formula (2).

[0103]

[0104] Here, F(λ) is the λ-coupling potential function corresponding to F(A) when λ = 0 and F(B) when λ = 1. λ is an intermediate virtual state set on the path from bounding state A to bounding state B, between 0 and 1; ΔF represents the difference between the binding free energy of bounding state B and the binding free energy of bounding state A.

[0105] Optionally, in step S106, the preset coordination energy calculation method is a quantum mechanical method. When calculating the coordination energy between the coordination warhead of a molecular conformation and the coordination center of the target protein according to quantum mechanics, for the molecular conformations in the second molecular conformation set whose coordination energy needs to be calculated, the coordination energy between the coordination warhead of that molecular conformation and the coordination center of the target protein is calculated according to the following formula:

[0106] Coordination energy = G(first complex) – G(first coordination center) – G(first coordination warhead);

[0107] Where G(X) represents the free energy,

[0108] wherein X is the first complex, is a complex of the coordination warhead of the target molecule conformation and the coordination center of the target protein;

[0109] wherein X is the first coordination warhead, is the coordination warhead of the target molecule conformation;

[0110] wherein X is the first coordination center, is the coordination center of the target protein.

[0111] wherein G(X) is calculated according to H, T, S corresponding to X and G(X) = H-TS:

[0112] wherein H = E+k B T, and

[0113]

[0114] wherein H, T, S used in calculating G(first complex), G(first coordination center) and G(first coordination warhead) respectively are H, T, S corresponding to G(X) of each.

[0115] wherein H is Planck's constant, T is temperature, k B is Boltzmann constant, S is entropy, is Hamiltonian operator, E is total energy, are kinetic energy operator, potential energy operator, electron-electron interaction energy operator respectively, h 2 is reduced Planck's constant, m i is mass of particle i, r i is position of particle i, and Ψ is wave function of the system.

[0116] As Figure 2 shown, the present application also provides a device 20 for virtually screening coordination inhibitors, comprising a memory 21 and a processor 22, wherein the processor 22 is configured to execute the method for virtually screening coordination inhibitors as described above according to instructions stored in the memory 21.

[0117] As Figure 3 shown, the present application also provides a device 30 for virtually screening coordination inhibitors, comprising:

[0118] a collecting module 301 configured to obtain a plurality of candidate ligand molecules containing at least one coordination warhead in a set of coordination warheads;

[0119] The first screening module 302 is configured to perform molecular docking of the plurality of candidate ligand molecules with the target protein respectively, to obtain a plurality of molecular conformations of the plurality of candidate ligand molecules after the molecular docking with the target protein respectively, and to screen a first set of molecular conformations from the plurality of molecular conformations according to distances between coordination warheads in the plurality of molecular conformations and coordination centers of the target protein.

[0120] The first obtaining module 303 is configured to obtain first binding free energies of the molecular conformations in the first set of molecular conformations after the molecular docking with the target protein according to a first binding free energy calculation method.

[0121] The second screening module 304 is configured to screen a second set of molecular conformations from the first set of molecular conformations according to the first binding free energies.

[0122] The third screening module 305 is configured to screen a third set of molecular conformations from the second set of molecular conformations, the third set of molecular conformations including target molecular conformations that satisfy a first preset condition on second binding free energies and / or a second preset condition on coordination energies.

[0123] The determining module 306 is configured to determine a coordination inhibitor according to the third set of molecular conformations.

[0124] The second binding free energy is a binding free energy of the target molecular conformations after the molecular docking with the target protein, which is calculated according to a second binding free energy calculation method.

[0125] The coordination energy is a coordination energy between the coordination warheads of the target molecular conformations and the coordination centers of the target protein, which is calculated according to a preset coordination energy calculation method.

[0126] Optionally, the screening of the first set of molecular conformations from the plurality of molecular conformations according to the distances between the coordination warheads and the coordination centers of the target protein includes:

[0127] The molecular conformations of the candidate ligand molecules in the plurality of molecular conformations, in which the distances between the coordination warheads and the coordination centers of the target protein are less than a distance threshold, are screened out to form the first set of molecular conformations.

[0128] Optionally, the second binding free energy calculation method has a higher calculation accuracy than the first binding free energy calculation method, and the first binding free energy calculation method has a higher calculation speed than the second binding free energy calculation method.

[0129] Optionally, the preset coordination energy calculation method is a quantum mechanics method.

[0130] Optionally, the calculation of the coordination energy between the coordination warhead of the target molecule conformation and the coordination center of the target protein according to the preset coordination energy calculation method comprises:

[0131] The coordination energy between the coordination warhead of the target molecule conformation and the coordination center of the target protein is calculated according to the following formula:

[0132] Coordination energy = G (first complex) - G (first coordination center) - G (first coordination warhead);

[0133] Wherein, G (X) represents the free energy of X;

[0134] Wherein, when X is the first complex, it is a complex formed by the coordination warhead of the target molecule conformation and the coordination center of the target protein;

[0135] Wherein, when X is the first coordination warhead, it is the coordination warhead of the target molecule conformation;

[0136] Wherein, when X is the first coordination center, it is the coordination center of the target protein.

[0137] Optionally, the calculation of the coordination energy between the coordination warhead of the target molecule conformation and the coordination center of the target protein according to the preset coordination energy calculation method further comprises:

[0138] G (X) is calculated according to H, T, S and G (X) = H-TS corresponding to X;

[0139] Wherein, H = E + k B T, and

[0140]

[0141] Wherein, H is the enthalpy, T is the temperature, S is the entropy, k B is the Boltzmann constant, is the Hamiltonian operator, E is the total energy, respectively, are the kinetic energy operator, potential energy operator and electron-electron interaction energy operator, h 2 is the reduced Planck constant, m i is the mass of particle i, r i is the position of particle i, and Ψ is the wave function of the system.

[0142] Optionally, the second binding free energy calculation method is a free energy perturbation method or a thermodynamic integration method.

[0143] Optionally, the target molecule conformation set that satisfies the first preset condition of the second binding free energy and / or the second preset condition of the coordination energy is selected from the second molecule conformation set to form a third molecule conformation set, which comprises:

[0144] screening the second molecular conformation set to obtain target molecular conformations satisfying the first preset condition of the second binding free energy and / or the second preset condition of the coordination energy, to form a third molecular conformation set.

[0145] screening the second molecular conformation set to obtain target molecular conformations satisfying the first preset condition of the second binding free energy and / or the second preset condition of the coordination energy, to form a third molecular conformation set.

[0146] Optionally, the screening the second molecular conformation set to obtain target molecular conformations satisfying the first preset condition of the second binding free energy and / or the second preset condition of the coordination energy, to form a third molecular conformation set, comprises:

[0147] screening the second molecular conformation set to obtain second candidate molecular conformations satisfying the second preset condition of the coordination energy, to form a second candidate molecular conformation set;

[0148] screening the second candidate molecular conformation set to obtain target molecular conformations satisfying the first preset condition of the second binding free energy, to form a third molecular conformation set.

[0149] Optionally, the screening the second molecular conformation set to obtain target molecular conformations satisfying the first preset condition of the second binding free energy and / or the second preset condition of the coordination energy, to form a third molecular conformation set, comprises:

[0150] screening the second molecular conformation set to obtain first candidate molecular conformations satisfying the first preset condition of the second binding free energy, to form a first candidate molecular conformation set;

[0151] screening the second molecular conformation set to obtain second candidate molecular conformations satisfying the second preset condition of the coordination energy, to form a second candidate molecular conformation set;

[0152] determining molecular conformations simultaneously located in the first candidate molecular conformation set and the second candidate molecular conformation set as target molecular conformations, to form a third molecular conformation set.

[0153] Optionally, the first binding free energy calculation method is to calculate the binding free energy according to the following function:

[0154] ΔG binding = ΔG0+ ΔG hbond Σ iI g1(Δr)g2(Δα)+ΔG metal Σ aM f(r aM )+ΔG lipo Σ lL f(r lL )

[0155] +ΔG rot Hrot ; wherein

[0156] AG0is obtained by multiple linear regression;

[0157] AG hbond ∑ iI g1(Δr)g2(Δα) is the hydrogen bond term, ∑ iI g1(Δr)g2(Δα) is used to calculate the complementarity of all hydrogen bonds between ligand atom i and acceptor atom I, g1(Δr) is a function of the hydrogen bond distance, g2(Δα) is a function of the hydrogen bond angle;

[0158] AG metal ∑ aM f(r aM ) is the metal term, ∑ aM f(r aM ) is used to calculate all acceptor and acceptor / donor atoms a in the ligand and any metal atoms M in the acceptor, f(r aM ) is a function of the distance of the metal atom to the acceptor / donor atoms in the ligand;

[0159] AG lipo ∑ lL f(r lL ) is the hydrophobic term, ∑ lL f(r lL ) is used to calculate all lipophilic ligand atoms I and all lipophilic acceptor atoms L, f(r lL ) is a function of the distance between the hydrophobic atoms;

[0160] AG rot H rot is a frozen rotatable bond.

[0161] Furthermore, the method according to the present application can also be implemented as a computer program or computer program product comprising computer program code instructions for performing some or all of the steps of the above-mentioned method according to the present application.

[0162] Alternatively, the present application can also be implemented as a computer readable storage medium (or non-transitory machine readable storage medium or machine readable storage medium) having stored thereon executable code (or computer program or computer instruction code) which, when executed by a processor of an electronic device (or server, etc.), causes the processor to perform some or all of the steps of the above-mentioned method according to the present application.

[0163] Having described various embodiments of the application, it is to be understood that the above description is meant not to limit and not to encompass all of the possible embodiments. Many modifications and variations of this application can be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. It is intended that the scope of the application be defined by the scope of the patent and by the claims as allowed by the patent office, which can include adaptations based on the description, equivalents, and / or substitutions of elements individually or collectively to the entire disclosure.

Claims

1. A method for virtual screening of coordination inhibitors, characterized in that, include: Obtain multiple candidate ligand molecules that include at least one coordinated warhead from the coordinated warhead set; The candidate ligand molecules are respectively docked with the target protein to obtain multiple molecular conformations after docking of the candidate ligand molecules with the target protein molecules. Based on the distance between the coordination warhead in the plurality of molecular conformations and the coordination center of the target protein, a first set of molecular conformations is selected from the plurality of molecular conformations; The first binding free energy is obtained by calculating the first binding free energy by the first method. After each molecular conformation in the first molecular conformation set is docked with the target protein, the first binding free energy is obtained. Based on the first binding free energy, a second set of molecular conformations is selected from the first set of molecular conformations; The third molecular conformation set is formed by selecting target molecular conformations whose second binding free energy satisfies the first preset condition and / or whose coordination energy satisfies the second preset condition from the second molecular conformation set. The coordination inhibitor was determined based on the third molecular conformation set; Wherein, the second binding free energy is the binding free energy of the target molecule conformation after docking with the target protein, calculated according to the second binding free energy calculation method; The coordination energy is calculated using a preset coordination energy calculation method, which determines the coordination energy between the coordination warhead of the target molecule conformation and the coordination center of the target protein.

2. The method according to claim 1, characterized in that, The step of selecting a first set of molecular conformations from the plurality of molecular conformations based on the distance between the coordination warhead in the plurality of molecular conformations and the coordination center of the target protein includes: The molecular conformations of candidate ligand molecules in the plurality of molecular conformations in which the distance between the coordination warhead and the coordination center of the target protein is less than a distance threshold are screened out to form the first molecular conformation set.

3. The method according to claim 1, characterized in that, The calculation accuracy of the second combined free energy calculation method is higher than that of the first combined free energy calculation method, and the calculation speed of the first combined free energy calculation method is higher than that of the second combined free energy calculation method. and / or The preset coordination energy calculation method is a quantum mechanical method.

4. The method according to claim 3, characterized in that, The calculation of the coordination energy between the coordination warhead of the target molecule conformation and the coordination center of the target protein according to the preset coordination energy calculation method includes: The coordination energy between the coordination warhead of the target molecule conformation and the coordination center of the target protein is calculated using the following formula: Coordination energy = G(first complex) – G(first coordination center) - G(first coordination warhead); Where G(X) represents the free energy of X; Wherein, when X is the first complex, it is a complex formed by the coordination warhead of the target molecule conformation and the coordination center of the target protein; Wherein, when X is the first coordination warhead, it is the coordination warhead of the target molecule conformation; Wherein, when X is the first coordination center, it is the coordination center of the target protein.

5. The method according to claim 4, characterized in that, The step of calculating the coordination energy between the coordination warhead of the target molecule conformation and the coordination center of the target protein according to a preset coordination energy calculation method further includes: G(X) is calculated based on H, T, S corresponding to X and G(X) = H - TS: Where H=E+ T, and Where H is enthalpy, T is temperature, and S is entropy. Boltzmann's constant, Let E be the Hamiltonian operator, and E be the total energy. These are the kinetic energy operator, potential energy operator, and electron-electron interaction energy operator, respectively, h 2 To reduce Planck's constant, Let i be the mass of particle i. Let Ψ be the position of particle i, and Ψ be the wave function of the system.

6. The method according to claim 1, characterized in that, The second method for calculating combined free energy is either the free energy perturbation method or the thermodynamic integral method.

7. The method according to claim 1, characterized in that, The process of selecting target molecular conformations from the second molecular conformation set that satisfy the first preset condition for binding free energy and / or the second preset condition for coordination energy to form the third molecular conformation set includes: From the second set of molecular conformations, first candidate molecular conformations whose second binding free energy satisfies the first preset condition are selected to form a first candidate molecular conformation set; from the first set of candidate molecular conformations, target molecular conformations whose coordination energy satisfies the second preset condition are selected to form a third molecular conformation set; or From the second set of molecular conformations, second candidate molecular conformations whose coordination energies satisfy the second preset condition are selected to form a second candidate molecular conformation set; from the second set of candidate molecular conformations, target molecular conformations whose second binding free energy satisfies the first preset condition are selected to form a third molecular conformation set; or First candidate molecular conformations that satisfy the first preset condition for the second binding free energy are selected from the second molecular conformation set to form a first candidate molecular conformation set. Second candidate molecular conformations that satisfy the second preset condition for coordination energy are selected from the second molecular conformation set to form a second candidate molecular conformation set. Molecular conformations that are simultaneously located in the first candidate molecular conformation set and the second candidate molecular conformation set are determined as target molecular conformations and form a third molecular conformation set.

8. The method according to claim 1, characterized in that, The first method for calculating the binding free energy is to calculate the binding free energy based on the following function: G binding = G0 + G hbond Σ iI g1( r)g2( α)+ G metal Σ aM f(r aM ) + G lipo Σ lL f(r lL ) + G rot H rot ; in, G0 is obtained through multiple linear regression; G hbond Σ iI g1( r)g2( α) is the hydrogen bond term, Σ iI g1( r)g2( α) is used to calculate the complementarity probability of all hydrogen bonds between ligand atom i and acceptor atom I, g1( r) is a function of hydrogen bond distance, g2( α) is a function of the hydrogen bond angle; G metal Σ aM f(r aM ) represents the metallic term, Σ aM f(r aM ) is used to calculate all acceptors and acceptor / donor atoms a and any metal atoms M in the acceptor. aM ) is a function of the distance between the metal atom and the acceptor / donor atom in the ligand; G lipo Σ lL f(r lL ) represents the hydrophobic term, Σ lL f(r lL ) is used to calculate all lipophilic ligand atoms l and all lipophilic acceptor atoms L, f(r lL ) is a function of the distance between hydrophobic atoms; G rot H rot For frozen rotatable keys.

9. A device for virtual screening of coordination inhibitors, characterized in that, include: A collection module is used to acquire multiple candidate ligand molecules containing at least one coordination warhead in a coordination warhead set; The first screening module is used to perform molecular docking of the plurality of candidate ligand molecules with the target protein respectively, to obtain a plurality of molecular conformations after the plurality of candidate ligand molecules are docked with the target protein molecule respectively; and to screen out a first set of molecular conformations from the plurality of molecular conformations based on the distance between the coordination warhead in the plurality of molecular conformations and the coordination center of the target protein. The first acquisition module is used to acquire the first binding free energy of each molecular conformation in the first molecular conformation set after docking with the target protein according to the first binding free energy calculation method. The second screening module is used to screen out a second molecular conformation set from the first molecular conformation set based on the first binding free energy. The third screening module is used to screen out target molecular conformations whose second binding free energy satisfies the first preset condition and / or whose coordination energy satisfies the second preset condition from the second molecular conformation set as the third molecular conformation set; The determination module is used to determine the coordination inhibitor based on the third molecular conformation set; Wherein, the second binding free energy is the binding free energy of the target molecule conformation after docking with the target protein, calculated according to the second binding free energy calculation method; The coordination energy is calculated using a preset coordination energy calculation method, which determines the coordination energy between the coordination warhead of the target molecule conformation and the coordination center of the target protein.

10. A device for virtual screening of coordination inhibitors, characterized in that, It includes a memory and a processor, wherein the memory stores executable code, and when the executable code is processed by the processor, the processor can perform the method of any one of claims 1 to 8.

11. A computer-readable storage medium, characterized in that, The system stores executable code that, when executed by a processor, causes the processor to perform the method as described in any one of claims 1 to 8.

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