Binding activity ranking method, apparatus, device, medium, and use

Abstract

The present application relates to the technical field of computational biology, and particularly relates to a binding activity ranking method, device, equipment, medium and use. The binding activity ranking method provided by the present application screens the applicability of electrostatic complementarity scoring of each candidate molecule and a receptor protein by the polarity state of each difference group between each candidate molecule, the polarity state of the target protein surface region corresponding to each difference group and the contact area of each candidate molecule and a solvent molecule, screens out target candidate molecules suitable for electrostatic complementarity scoring, determines the electrostatic complementarity scoring value between each target candidate molecule and the receptor protein based on the electrostatic complementarity scoring method, and ranks the binding activity of each target candidate molecule and the receptor protein based on the electrostatic complementarity scoring value, which effectively solves the problem of low reliability of the evaluation result caused by poor applicability of the existing electrostatic complementarity scoring method to some small molecules and proteins.

Description

Technical Field

[0001] This invention relates to the field of computational biology, specifically to a method, apparatus, device, medium, and application for combining activity ranking. Background Technology

[0002] In the development of small molecule drugs, it is necessary to pay attention to the weak interactions between small molecules and proteins. Electrostatic interactions are one of the most important weak interactions and have a decisive influence on the biological activity of small molecules in many cases.

[0003] In the virtual screening phase of small molecule drug development, the most crucial task is ranking the binding activity between small molecules and proteins. Methods used include binding free energy calculation and docking scoring. However, binding free energy calculation typically requires significant computational resources, limiting its application in high-throughput screening; docking scoring is faster but less accurate. In contrast, electrostatic complementarity scoring (EC score) can rank small molecules by assessing the degree of electrostatic complementarity between them and proteins, achieving a speed comparable to docking scoring. Furthermore, in some systems, EC scores show a good correlation with the biological activity of small molecules.

[0004] However, the existing electrostatic complementary scoring method is not well-suited for some small molecules and proteins, resulting in low reliability of its evaluation results on the binding activity of small molecules and proteins, which limits its large-scale use in actual drug development. Summary of the Invention

[0005] Therefore, the technical problem to be solved by the present invention is to overcome the deficiency of the low reliability of the evaluation results of the binding activity of small molecules and proteins by the existing electrostatic complementary scoring method, thereby providing a binding activity ranking method, device, equipment, medium and application.

[0006] To this end, the present invention provides a binding activity ranking method, comprising the following operations: in response to obtaining at least one differential group among multiple candidate molecules, determining the target protein surface region corresponding to the differential group in each candidate molecule based on the complex structure of each candidate molecule and the receptor protein; determining the electrostatic complementarity scoring suitability of each candidate molecule with the receptor protein based on the polarity state of the differential group in the candidate molecule, the polarity state of the target protein surface region corresponding to the differential group in the candidate molecule, and the contact area between the candidate molecule and the solvent molecule; screening at least one target candidate molecule suitable for electrostatic complementarity scoring based on the electrostatic complementarity scoring suitability of each candidate molecule with the receptor protein, and determining the electrostatic complementarity score value between each target candidate molecule and the receptor protein using the electrostatic complementarity scoring method; and ranking the binding activities of each target candidate molecule with the receptor protein based on the electrostatic complementarity score value between each target candidate molecule and the receptor protein.

[0007] Optionally, the target protein surface region is a receptor protein surface region whose distance from any atom of the differential group is within a preset range. The step of determining the target protein surface region corresponding to the differential group in each candidate molecule based on the composite structure of each candidate molecule and the receptor protein includes: acquiring surface grid points of the receptor protein; determining the distance between each surface grid point of the receptor protein and any atom of the differential group in the candidate molecule based on the composite structure of the candidate molecule and the receptor protein; and using the region composed of surface grid points whose distance from any atom of the differential group in the candidate molecule is within a preset range as the target protein surface region corresponding to the differential group in the candidate molecule; wherein the preset range is less than or equal to 3.5 angstroms.

[0008] Optionally, determining the electrostatic complementarity scoring suitability of each candidate molecule and receptor protein based on the polarity state of the differentially expressed groups in the candidate molecule, the polarity state of the target protein surface region corresponding to the differentially expressed groups in the candidate molecule, and the contact area between the candidate molecule and the solvent molecules includes: determining whether the differentially expressed groups are polar groups based on the polarity state of the differentially expressed groups in the candidate molecule; determining whether the target protein surface region corresponding to the differentially expressed groups is a polar region based on the polarity state of the target protein surface region corresponding to the differentially expressed groups in the candidate molecule; determining whether the interaction between the candidate molecule and the solvent molecules is weaker than a preset state based on the contact area between the candidate molecule and the solvent molecules; and determining that the candidate molecule and receptor protein are suitable for electrostatic complementarity scoring when the differentially expressed groups are polar groups, the target protein surface region corresponding to the differentially expressed groups is a polar region, and the interaction between the candidate molecule and the solvent molecules is weaker than a preset state.

[0009] Optionally, determining whether a differential group is a polar group based on the polarity state of the differential group in the candidate molecule includes: determining whether there are polar atoms in the differential group based on the atom type of each atom in the differential group; determining the differential group as a polar group if polar atoms are found to be present in the differential group; and / or determining the differential group as a nonpolar group if polar atoms are found to be absent in the differential group.

[0010] Optionally, determining whether the target protein surface region corresponding to the differentially expressed group is a polar region based on the polarity state of the target protein surface region corresponding to the differentially expressed group in the candidate molecule includes: determining whether there are points in the target protein surface region with an absolute value of protein electrostatic potential greater than a preset electrostatic potential based on the protein electrostatic potential at each point in the target protein surface region, wherein the protein electrostatic potential is the electrostatic potential generated by the receptor protein at the current point; determining the target protein surface region as a polar region if it is determined that there are points in the target protein surface region with an absolute value of protein electrostatic potential greater than the preset electrostatic potential; and / or determining the target protein surface region as a non-polar region if it is determined that there are no points in the target protein surface region with an absolute value of protein electrostatic potential greater than the preset electrostatic potential.

[0011] Optionally, the contact area between the candidate molecule and the solvent molecule includes a first contact area between the candidate molecule and the solvent molecule in the composite state and a second contact area between the candidate molecule and the solvent molecule in the non-composite state. Determining whether the interaction between the candidate molecule and the solvent molecule is weaker than a preset state based on the contact area includes: determining the first contact area between the candidate molecule and the solvent molecule in the composite state and the second contact area between the candidate molecule and the solvent molecule in the non-composite state based on the molecular structure of the candidate molecule; determining whether the composite / non-composite solvent contact area ratio of the candidate molecule is less than a preset ratio based on the first contact area and the second contact area; determining that the interaction between the candidate molecule and the solvent molecule is weaker than a preset state if the composite / non-composite solvent contact area ratio is less than a preset ratio; and / or determining that the interaction between the candidate molecule and the solvent molecule is not weaker than a preset state if the composite / non-composite solvent contact area ratio is not less than a preset ratio.

[0012] Optionally, determining the electrostatic complementarity score between each target candidate molecule and the receptor protein using the electrostatic complementarity scoring method includes: determining the electrostatic complementarity score between the target candidate molecule and the receptor protein based on the molecular electrostatic potential and protein electrostatic potential at each point on the surface of the target candidate molecule, wherein the molecular electrostatic potential is the electrostatic potential generated by the target candidate molecule at the current point, and the protein electrostatic potential is the electrostatic potential generated by the receptor protein at the current point.

[0013] The present invention also provides a binding activity ranking device, comprising: a first processing module, configured to, in response to obtaining at least one differential group among multiple candidate molecules, determine the target protein surface region corresponding to the differential group in each candidate molecule based on the complex structure of each candidate molecule and the receptor protein; a second processing module, configured to, based on the polarity state of the differential group in the candidate molecule, the polarity state of the target protein surface region corresponding to the differential group in the candidate molecule, and the contact area between the candidate molecule and the solvent molecule, determine the electrostatic complementarity scoring suitability of each candidate molecule and the receptor protein; a third processing module, configured to, based on the electrostatic complementarity scoring suitability of each candidate molecule and the receptor protein, screen out at least one target candidate molecule suitable for electrostatic complementarity scoring, and determine the electrostatic complementarity score value between each target candidate molecule and the receptor protein using the electrostatic complementarity scoring method; and a fourth processing module, configured to, based on the electrostatic complementarity score value between each target candidate molecule and the receptor protein, rank the binding activity of each target candidate molecule and the receptor protein.

[0014] Optionally, the target protein surface region is a receptor protein surface region whose distance from any atom of the differential group is within a preset range. The first processing module includes: a first processing submodule for acquiring surface grid points of the receptor protein; a second processing submodule for determining the distance between each surface grid point of the receptor protein and any atom of the differential group in the candidate molecule based on the composite structure of the candidate molecule and the receptor protein; and a third processing submodule for using the region composed of surface grid points whose distance from any atom of the differential group in the candidate molecule is within a preset range as the target protein surface region corresponding to the differential group in the candidate molecule; wherein, the preset range is less than or equal to 3.5 angstroms.

[0015] Optionally, the second processing module includes: a fourth processing submodule, used to determine whether the differentially expressed group is a polar group based on the polarity state of the differentially expressed group in the candidate molecule; a fifth processing submodule, used to determine whether the target protein surface region corresponding to the differentially expressed group is a polar region based on the polarity state of the target protein surface region corresponding to the differentially expressed group in the candidate molecule; a sixth processing submodule, used to determine whether the interaction between the candidate molecule and the solvent molecule is weaker than a preset state based on the contact area between the candidate molecule and the solvent molecule; and a seventh processing submodule, used to determine that the candidate molecule and the receptor protein are suitable for electrostatic complementary scoring when the differentially expressed group is a polar group, the target protein surface region corresponding to the differentially expressed group is a polar region, and the interaction between the candidate molecule and the solvent molecule is weaker than a preset state.

[0016] Optionally, the fourth processing submodule includes: a first processing unit, used to determine whether there are polar atoms in the differential group based on the atom type of each atom in the differential group; a second processing unit, used to determine that the differential group is a polar group if polar atoms are found in the differential group; and / or a third processing unit, used to determine that the differential group is a nonpolar group if polar atoms are found not in the differential group.

[0017] Optionally, the fifth processing submodule includes: a fourth processing unit, configured to determine whether there are points in the target protein surface region with an absolute value of protein electrostatic potential greater than a preset electrostatic potential based on the protein electrostatic potential at each point in the target protein surface region, wherein the protein electrostatic potential is the electrostatic potential generated by the receptor protein at the current point; a fifth processing unit, configured to determine the target protein surface region as a polar region if it is determined that there are points in the target protein surface region with an absolute value of protein electrostatic potential greater than the preset electrostatic potential; and / or a sixth processing unit, configured to determine the target protein surface region as a non-polar region if it is determined that there are no points in the target protein surface region with an absolute value of protein electrostatic potential greater than the preset electrostatic potential.

[0018] Optionally, the contact area between the candidate molecule and the solvent molecule includes a first contact area between the candidate molecule and the solvent molecule in a composite state and a second contact area between the candidate molecule and the solvent molecule in a non-composite state. The sixth processing submodule includes: a seventh processing unit, used to determine, based on the molecular structure of the candidate molecule, the first contact area between the candidate molecule and the solvent molecule in a composite state and the second contact area between the candidate molecule and the solvent molecule in a non-composite state; an eighth processing unit, used to determine, based on the first contact area and the second contact area, whether the composite / non-composite solvent contact area ratio of the candidate molecule is less than a preset ratio; a ninth processing unit, used to determine, if the composite / non-composite solvent contact area ratio is less than the preset ratio, that the interaction between the candidate molecule and the solvent molecule is weaker than a preset state; and / or a tenth processing unit, used to determine, if the composite / non-composite solvent contact area ratio is not less than the preset ratio, that the interaction between the candidate molecule and the solvent molecule is not weaker than a preset state.

[0019] Optionally, the third processing module includes an eighth processing submodule, used to determine the electrostatic complementarity score between the target candidate molecule and the receptor protein based on the molecular electrostatic potential and protein electrostatic potential at each point on the surface of the target candidate molecule using an electrostatic complementarity scoring method, wherein the molecular electrostatic potential is the electrostatic potential generated by the target candidate molecule at the current point, and the protein electrostatic potential is the electrostatic potential generated by the receptor protein at the current point.

[0020] The present invention also provides an electronic device / mobile terminal / server, comprising: a memory and a processor, wherein the memory and the processor are communicatively connected to each other, the memory stores computer instructions, and the processor executes the computer instructions to perform the combined activity sorting method described above.

[0021] The present invention also provides a computer-readable storage medium storing computer instructions for causing the computer to perform the combined liveness sorting method described in any of the preceding claims.

[0022] The present invention also provides the use of the binding activity sequencing method described in any of the above claims, or the electronic device / mobile terminal / server described in the above claims, or the computer-readable storage medium described in the above claims in protein design, drug screening, small molecule design, or small molecule chemical synthesis.

[0023] The technical solution of this invention has the following advantages:

[0024] The binding activity ranking method provided by this invention screens the applicability of electrostatic complementarity scoring between candidate molecules and receptor proteins based on the polarity state of the differential groups among candidate molecules, the polarity state of the target protein surface region corresponding to each differential group, and the contact area between each candidate molecule and solvent molecules. This screens out target candidate molecules suitable for the electrostatic complementarity scoring method, determines the electrostatic complementarity score between each target candidate molecule and receptor protein based on the electrostatic complementarity scoring method, and ranks the binding activities of each target candidate molecule and receptor protein based on the electrostatic complementarity score. This effectively solves the problem of low reliability of evaluation results caused by the poor applicability of existing electrostatic complementarity scoring methods to some small molecules and proteins.

[0025] Therefore, the method of the present invention can relatively accurately rank the binding activities of candidate molecules and receptor proteins based on electrostatic complementary scoring, with high reliability, which lays the foundation for its large-scale use in actual drug development. Attached Figure Description

[0026] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0027] Figure 1 A flowchart illustrating a method combining liveness ranking is shown schematically.

[0028] Figure 2 A flowchart illustrating another approach combining liveness ranking is shown schematically.

[0029] Figure 3 These are the electrostatic complementarity scores and IC values ​​corresponding to the six candidate small molecule drugs in the experimental examples of this invention. 50 Correlation curves between values;

[0030] Figure 4 These are the electrostatic complementarity scores and IC values ​​corresponding to the 11 candidate small molecule drugs in the experimental examples of this invention. 50 Correlation curves between values;

[0031] Figure 5 A block diagram illustrating an active sorting device is shown schematically.

[0032] Figure 6 A block diagram of an electronic device for performing a combined liveness sorting method is shown schematically. Detailed Implementation

[0033] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0034] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0035] Example 1

[0036] Figure 1 A flowchart illustrating an activity-based ranking method is shown, such as... Figure 1 As shown, method 100 may include operations S101 to S104.

[0037] In operation S101, in response to obtaining at least one differential group among multiple candidate molecules, the target protein surface region corresponding to the differential group in each candidate molecule is determined based on the complex structure of each candidate molecule and the receptor protein.

[0038] For example, each candidate molecule can be a small molecule with the same parent nucleus, and the differentiating group can be a substituent group in the structure of each candidate molecule that is not completely the same as the parent nucleus. The differentiating groups between each candidate molecule and other candidate molecules can be determined by structural comparison or by specifying the parent nucleus of the molecule.

[0039] Optionally, the composite structure of the candidate molecule and the receptor protein can be obtained by combining the candidate molecule structure and the receptor protein structure using software such as molecular docking software, including DOCK, Autodock, and FlexX. The candidate molecule structure can be, for example, the crystal structure of the candidate molecule or the structure optimized using quantitative software such as Gaussian. The receptor protein structure can be, for example, the crystal structure of the receptor protein or the structure calculated using molecular dynamics software such as Amber. Both the candidate molecule structure and the receptor protein structure can be saved in advance as PDB files.

[0040] Optionally, the target protein surface region can be a receptor protein surface region whose distance from any atom of the differential group is within a preset range. The step of determining the target protein surface region corresponding to the differential group in each candidate molecule based on the composite structure of each candidate molecule and the receptor protein can include: obtaining the surface grid of the receptor protein; determining the distance between each surface grid of the receptor protein and any atom of the differential group in the candidate molecule based on the composite structure of the candidate molecule and the receptor protein; and taking the region composed of surface grids whose distance from any atom of the differential group in the candidate molecule is within a preset range as the target protein surface region corresponding to the differential group in the candidate molecule.

[0041] Optionally, the surface grid of the receptor protein can be generated and obtained based on the definition of the Connolly molecular surface. The preset range can be selected within a certain range, for example, the preset range can be less than or equal to 3.5 angstroms.

[0042] In operation S102, the electrostatic complementarity scoring applicability of each candidate molecule to the receptor protein is determined based on the polarity state of the differential groups in the candidate molecule, the polarity state of the target protein surface region corresponding to the differential groups in the candidate molecule, and the contact area between the candidate molecule and the solvent molecule.

[0043] The inventors discovered that the polarity of the differential groups in the candidate molecules, the polarity of the target protein surface region corresponding to the differential groups in the candidate molecules, and the contact area between the candidate molecules and the solvent molecules are several key factors affecting the applicability of the electrostatic complementary scoring method. Therefore, by screening candidate molecules based on these factors, it is possible to select candidate molecules suitable for the electrostatic complementary scoring method.

[0044] Further research by the inventors revealed that when the differential group in the candidate molecule is a nonpolar group, and / or when the target protein surface region corresponding to the differential group in the candidate molecule is a nonpolar region, and / or when there is a strong interaction between the candidate molecule and the solvent molecule, the binding activity between the candidate molecule and the receptor protein is not suitable for evaluation using the electrostatic complementary scoring method.

[0045] In operation S103, based on the applicability of electrostatic complementarity scoring between each candidate molecule and the receptor protein, at least one target candidate molecule suitable for electrostatic complementarity scoring is screened out, and the electrostatic complementarity scoring value between each target candidate molecule and the receptor protein is determined using the electrostatic complementarity scoring method.

[0046] Optionally, determining the electrostatic complementarity score between each target candidate molecule and the receptor protein using the electrostatic complementarity scoring method may include: determining the electrostatic complementarity score between the target candidate molecule and the receptor protein based on the molecular electrostatic potential and protein electrostatic potential at each point on the surface of the target candidate molecule, wherein the molecular electrostatic potential is the electrostatic potential generated by the target candidate molecule at the current point, and the protein electrostatic potential is the electrostatic potential generated by the receptor protein at the current point.

[0047] For example, the molecular electrostatic potential can be the sum of the electrostatic potentials generated at the current position by all charges within the target candidate molecule, and the protein electrostatic potential can be the sum of the electrostatic potentials generated at the current position by all charges within the receptor protein. The charge distribution within the target candidate molecule or receptor protein can be obtained through machine learning methods, molecular force field methods, or quantum chemical methods, etc., which will not be elaborated here.

[0048] Optionally, the molecular electrostatic potential or the protein electrostatic potential can be calculated using the Coulomb formula:

[0049]

[0050] In the above formula, ESP can represent the molecular electrostatic potential or the protein electrostatic potential, and ε represents the dielectric constant. When ESP represents the molecular electrostatic potential, q i r represents the value of the i-th charge within the target candidate molecule. i q represents the distance from the i-th charge within the target candidate molecule to the current location; when ESP represents the protein electrostatic potential, q i r represents the value of the i-th charge within the receptor protein. i This represents the distance from the i-th charge within the protein to the current location.

[0051] Optionally, the electrostatic complementarity score can be calculated using Pearson's R-coefficient method or the electrostatic complementarity score calculation method defined by Rathi et al. For example, the formula for Pearson's R-coefficient method is as follows:

[0052]

[0053] In the above formula, EC represents the electrostatic complementarity score, and j represents the j-th site on the surface of the target candidate molecule. This represents the electrostatic potential generated by the target candidate molecule at the j-th position. This represents the electrostatic potential generated by the receptor protein at the j-th site. and Let $\mathbf$ and $\mathbf$ represent the average and variance of the electrostatic potential generated at various points on the surface of the target candidate molecule, respectively. and These represent the average and variance of the electrostatic potential generated by the receptor protein at various points on the surface of the target candidate molecule, respectively.

[0054] In operation S104, the binding activity of each target candidate molecule to the receptor protein is ranked based on the electrostatic complementarity score between each target candidate molecule and the receptor protein.

[0055] Optionally, the electrostatic complementarity score between each target candidate molecule and the receptor protein is positively correlated with the binding activity of each target candidate molecule to the receptor protein.

[0056] Example 2

[0057] Figure 2 A flowchart illustrating another approach combining activity ranking is shown, such as... Figure 2 As shown, method 200 may include operation S101, operation S201 to operation S204 and operation S103 to operation S104.

[0058] In operation S101, in response to obtaining at least one differential group among multiple candidate molecules, the target protein surface region corresponding to each differential group is determined based on the complex structure of each candidate molecule and the receptor protein. Operation S101 in this embodiment is detailed in Example 1 and will not be repeated here.

[0059] In operation S201, based on the polarity state of the differential groups in the candidate molecule, it is determined whether the differential groups are polar groups.

[0060] For example, determining whether a differential group is a polar group based on the polarity state of the differential group in the candidate molecule includes: determining whether there are polar atoms in the differential group based on the atom type of each atom in the differential group; determining the differential group as a polar group if polar atoms are found to be present in the differential group; and / or determining the differential group as a nonpolar group if polar atoms are found to be absent in the differential group.

[0061] In operation S202, based on the polarity state of the target protein surface region corresponding to the differential group in the candidate molecule, it is determined whether the target protein surface region corresponding to the differential group is a polar region.

[0062] For example, determining whether the target protein surface region corresponding to the differentially expressed group is a polar region based on the polarity state of the target protein surface region corresponding to the differentially expressed group in the candidate molecule includes: determining whether there are points in the target protein surface region with an absolute value of protein electrostatic potential greater than a preset electrostatic potential based on the protein electrostatic potential at each point in the target protein surface region, wherein the protein electrostatic potential is the electrostatic potential generated by the receptor protein at the current point; determining the target protein surface region as a polar region if it is determined that there are points in the target protein surface region with an absolute value of protein electrostatic potential greater than the preset electrostatic potential; and / or determining the target protein surface region as a non-polar region if it is determined that there are no points in the target protein surface region with an absolute value of protein electrostatic potential greater than the preset electrostatic potential.

[0063] Optionally, the electrostatic potential of the protein at each point on the surface of the target protein refers to the electrostatic potential generated by the receptor protein at each point on the surface of the target protein. Specifically, it refers to the electrostatic potential generated by all charges inside the receptor protein at each point on the surface of the target protein. The electrostatic potential of the protein at each point on the surface of the target protein can be calculated according to the Coulomb formula, as detailed in operation S103 of Example 1, and will not be repeated here.

[0064] Optionally, the value of the preset electrostatic potential can vary within a certain range. For example, the value of the preset electrostatic potential can be 15 kcal / (mol*e) or higher.

[0065] In operation S203, based on the contact area between the candidate molecule and the solvent molecule, it is determined whether the interaction between the candidate molecule and the solvent molecule is weaker than the preset state.

[0066] For example, the contact area between the candidate molecule and the solvent molecule includes a first contact area between the candidate molecule and the solvent molecule in a composite state and a second contact area between the candidate molecule and the solvent molecule in a non-composite state. Determining whether the interaction between the candidate molecule and the solvent molecule is weaker than a preset state based on the contact area includes: determining the first contact area between the candidate molecule and the solvent molecule in a composite state and the second contact area between the candidate molecule and the solvent molecule in a non-composite state based on the molecular structure of the candidate molecule; determining whether the composite / non-composite solvent contact area ratio of the candidate molecule is less than a preset ratio based on the first contact area and the second contact area; determining that the interaction between the candidate molecule and the solvent molecule is weaker than a preset state if the composite / non-composite solvent contact area ratio is less than the preset ratio; and / or determining that the interaction between the candidate molecule and the solvent molecule is not weaker than a preset state if the composite / non-composite solvent contact area ratio is not less than the preset ratio.

[0067] Optionally, the first contact area between the candidate molecule and the solvent molecule in the recombination state and the second contact area between the candidate molecule and the solvent molecule in the non-recognition state can be calculated using common methods in the field. For example, existing algorithms, software, or programs can be used for calculation. For instance, calculation tools such as the PMV algorithm, VMD algorithm, Material Studio software, and solvent accessible surface area calculator can be used for calculation.

[0068] Optionally, the preset ratio can vary within a certain range. For example, the preset ratio can be 0.2 to 0.4. For instance, the preset ratio can be 0.2, 0.3, or 0.4.

[0069] In this embodiment, the execution order of operations S201 to S203 is not limited, and operations S201 to S203 can be executed in any order.

[0070] In operation S204, under the conditions that the differential group is a polar group, the target protein surface region corresponding to the differential group is a polar region, and the interaction between the candidate molecule and the solvent molecule is weaker than the preset state, it is determined that the candidate molecule and the receptor protein are suitable for electrostatic complementary scoring.

[0071] In operation S103, based on the applicability of electrostatic complementarity scoring between each candidate molecule and the receptor protein, at least one target candidate molecule suitable for electrostatic complementarity scoring is determined, and the electrostatic complementarity score value between each target candidate molecule and the receptor protein is determined using the electrostatic complementarity scoring method. Operation S103 in this embodiment is detailed in Example 1 and will not be repeated here.

[0072] In operation S104, the binding activity of each target candidate molecule to the receptor protein is ranked based on the electrostatic complementarity score between each target candidate molecule and the receptor protein. Operation S104 in this embodiment is detailed in Example 1 and will not be repeated here.

[0073] Example 3

[0074] This embodiment provides a method for screening small molecule drugs, wherein the target protein has a PDB ID of 6CKR, and the candidate small molecule drugs are numbered 18, 19, 20, 21, 25, 26, 27, 28, 29, 31, and 32, and each candidate small molecule drug has the following core structure:

[0075]

[0076] In the above structural formula, X and Y represent the differentiating groups between the candidate small molecule drugs, and the types of differentiating groups are shown in Table 1.

[0077] Table 1. Differentiating group types among candidate small molecule drugs

[0078] serial number X Y 18 <![CDATA[SO2NH2]]> H 19 <![CDATA[SO2NHEt]]> H 20 <![CDATA[SO2NHBn]]> H 21 <![CDATA[NHSO2Me]]> H 25 <![CDATA[NH2]]> H 26 <![CDATA[NMeSO2Me]]> H 27 <![CDATA[CH2NHSO2Me]]> H 28 <![CDATA[NHSO2NMe2]]> H 29 <![CDATA[NHSO2Me]]> Me 31 <![CDATA[NHSO2Me]]> Ph 32 <![CDATA[NHSO2Me]]> 1-methylpyrazol-4-yl

[0079] The small molecule drug screening method in this embodiment includes the following operations:

[0080] (1) Use docking software (AutoDock) to read the PDB structure files of each candidate small molecule drug and the target protein, and dock to generate docking structures corresponding to each candidate small molecule drug.

[0081] (2) Based on each docking structure, the target protein surface region with a distance of less than 3.5 angstroms from any atom of the differential group shown in Table 1 is determined in the docking structure corresponding to each candidate small molecule drug.

[0082] (3) Determine whether there are polar atoms in the differential groups shown in Table 1, and screen out the candidate small molecule drugs corresponding to the differential groups with polar atoms, numbered 18, 19, 20, 21, 25, 26, 27, 28, 29, 31 and 32 in sequence;

[0083] (4) Calculate the electrostatic potential of the target protein at each point on the surface of the target protein corresponding to the differential group of the above 11 candidate small molecule drugs according to the Coulomb formula, and take the extreme value as esp_extre(+) or esp_extre(-), as shown in Table 2.

[0084] (5) The solvent accessible surface area calculation tool was used to calculate the first contact area between the above 11 candidate small molecule drugs and solvent molecules (water molecules) in the composite state and the second contact area between the drugs and solvent molecules in the non-composite state, and the composite / non-composite solvent contact area ratio was calculated and denoted as sas_ratio, as shown in Table 2.

[0085] (6) According to the preset electrostatic potential = 20kcal / (mol*e) and preset ratio = 0.35, the candidate small molecule drugs listed in Table 2 were screened. It can be seen that the sas_ratio values ​​of candidate small molecule drugs 18, 21, 26, 27, 29 and 32 are all less than the preset ratio, and the absolute values ​​of the corresponding protein electrostatic potential esp_extre(+) or esp_extre(-) are all greater than the preset electrostatic potential. Therefore, it is determined that the interaction between the above 6 candidate small molecule drugs and the target protein is suitable for electrostatic complementarity scoring.

[0086] (7) Calculate the electrostatic complementarity scores between the six candidate small molecule drugs and the target protein in step (6) according to Pearson's R coefficient method, as shown in Table 3.

[0087] Table 2. sas_ratio and esp_extre values ​​for 11 candidate small molecule drugs.

[0088] candidate small molecule drugs sas_ratio esp_extre(+) esp_extre(-) 18 0.05 91.57 -78.49 19 0.68 7.63 -5.07 20 0.53 7.63 -7.32 21 0.04 27.83 -78.49 25 0.13 14.27 -16.23 26 0.06 27.83 -78.49 27 0.06 27.83 -78.49 28 0.54 7.63 -4.87 29 0.22 27.83 -78.49 31 0.35 27.83 -78.49 32 0.34 27.83 -78.49

[0089] Table 3. Electrostatic complementarity scores between the six candidate small molecule drugs and the target protein.

[0090]

[0091]

[0092] Comparative Example 1

[0093] The electrostatic complementarity scores between the 11 candidate small molecule drugs (18, 19, 20, 21, 25, 26, 27, 28, 29, 31 and 32) and the target protein (6CKR) in step (3) of Example 3 were calculated according to Pearson's R coefficient method, as shown in Table 4.

[0094] Table 4. Electrostatic complementarity scores between 11 candidate small molecule drugs and target proteins

[0095] candidate small molecule drugs Electrostatic Complementary Scoring Value 18 0.400 19 0.356 20 0.391 21 0.427 25 0.475 26 0.416 27 0.398 28 0.360 29 0.442 31 0.457 32 0.435

[0096] Experimental Example

[0097] The half-maximal inhibitory concentration (IC50) of the 11 candidate small molecule drugs (18, 19, 20, 21, 25, 26, 27, 28, 29, 31 and 32) in step (3) of Example 3 was measured against the target protein (6CKR). 50 The values ​​and test results are shown in Table 5.

[0098] Table 5. Half-inhibitory concentration (IC50) of 11 candidate small molecule drugs against the target protein 50 value

[0099]

[0100]

[0101] Based on the contents of Tables 3 and 5, the electrostatic complementarity scores between the six candidate small molecule drugs (18, 21, 26, 27, 29, and 32) and the target protein (6CKR) in step (6) of Example 3, as well as their half-inhibitory concentrations (IC50) for the target protein (6CKR), were plotted. 50 Correlation curves between values, such as Figure 3 As shown.

[0102] Based on the contents of Tables 4 and 5, electrostatic complementarity scores between the 11 candidate small molecule drugs (18, 19, 20, 21, 25, 26, 27, 28, 29, 31, and 32) in step (3) of Example 3 and the target protein (6CKR) and their half-inhibitory concentration (IC50) for the target protein (6CKR) were plotted. 50 Correlation curves between values, such as Figure 4 As shown.

[0103] Depend on Figure 3 and Figure 4 It can be seen that, after screening, the electrostatic complementarity score between the candidate small molecule drug and the target protein and its half-inhibitory concentration (IC50) on the target protein are significant. 50 The correlation coefficient between the values ​​increased from 0.01 to 0.71.

[0104] Figure 5 A block diagram illustrating an active sorting device is shown, such as Figure 5 As shown, the active sorting device 500 may include a first processing module 501, a second processing module 502, a third processing module 503, and a fourth processing module 504.

[0105] The first processing module 501 is used to, in response to obtaining at least one differential group among multiple candidate molecules, determine the target protein surface region corresponding to the differential group in each candidate molecule based on the complex structure of each candidate molecule and the receptor protein; the second processing module 502 is used to determine the electrostatic complementarity scoring suitability of each candidate molecule with the receptor protein based on the polarity state of the differential group in the candidate molecule, the polarity state of the target protein surface region corresponding to the differential group in the candidate molecule, and the contact area between the candidate molecule and the solvent molecule; the third processing module 503 is used to, based on the electrostatic complementarity scoring suitability of each candidate molecule with the receptor protein, screen out at least one target candidate molecule suitable for electrostatic complementarity scoring, and determine the electrostatic complementarity score value between each target candidate molecule and the receptor protein using the electrostatic complementarity scoring method; the fourth processing module 504 is used to rank the binding activity of each target candidate molecule with the receptor protein based on the electrostatic complementarity score value between each target candidate molecule and the receptor protein.

[0106] Figure 6 A block diagram of an electronic device for performing a combined liveness ranking method is shown schematically, such as Figure 6 As shown, the electronic device 600 may include a processor 601 and a memory 602, wherein the processor 601 and the memory 602 may be connected via a bus or other means. Figure 6 Taking the connection via bus 603 as an example.

[0107] Processor 601 may be a central processing unit (CPU). Processor 601 may also be other general-purpose processors, digital signal processors (DSPs), application-specific integrated circuits (ASICs), field-programmable gate arrays (FPGAs), or other programmable logic devices, discrete gate or transistor logic devices, discrete hardware components, or combinations thereof.

[0108] Memory 602, as a non-transitory computer-readable storage medium, can be used to store non-transitory software programs, non-transitory computer-executable programs, and modules, such as the program instructions / modules corresponding to the activity determination method in this embodiment of the invention (e.g., Figure 5 The first processing module 501, the second processing module 502, the third processing module 503, and the fourth processing module 504 are shown. The processor 601 executes various functional applications and data processing by running non-transitory software programs, instructions, and modules stored in the memory 602, thereby implementing the binding activity determination method in the above method embodiments.

[0109] The memory 602 may include a program storage area and a data storage area. The program storage area may store the operating system and applications required for at least one function; the data storage area may store data created by the processor 601, etc. Furthermore, the memory 602 may include high-speed random access memory and may also include non-transitory memory, such as at least one disk storage device, flash memory device, or other non-transitory solid-state storage device. In some embodiments, the memory 602 may optionally include memory remotely located relative to the processor 601, and these remote memories may be connected to the processor 601 via a network. Examples of such networks include, but are not limited to, the Internet, corporate intranets, local area networks, mobile communication networks, and combinations thereof.

[0110] The one or more modules are stored in the memory 602, and when executed by the processor 601, they perform actions such as... Figure 1-2 The binding activity determination method in the illustrated embodiment.

[0111] For specific details regarding the aforementioned electronic devices, please refer to the relevant documentation. Figures 1 to 2 The relevant descriptions and effects in the illustrated embodiments are for understanding purposes only and will not be repeated here.

[0112] Those skilled in the art will understand that all or part of the processes in the methods of the above embodiments can be implemented by a computer program instructing related hardware. The program can be stored in a computer-readable storage medium, and when executed, it can include the processes of the embodiments of the above methods. The storage medium can be a magnetic disk, optical disk, read-only memory (ROM), random access memory (RAM), flash memory, hard disk drive (HDD), or solid-state drive (SSD), etc.; the storage medium can also include combinations of the above types of memory.

[0113] Although embodiments of the invention have been described in conjunction with the accompanying drawings, those skilled in the art can make various modifications and variations without departing from the spirit and scope of the invention, and such modifications and variations all fall within the scope defined by the appended claims.

[0114] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method combining activity ranking, characterized in that, This includes the following operations: In response to obtaining at least one differential group among multiple candidate molecules, the target protein surface region corresponding to the differential group in each candidate molecule is determined based on the complex structure of each candidate molecule and the receptor protein. Based on the polarity state of the differential groups in the candidate molecules, the polarity state of the target protein surface region corresponding to the differential groups in the candidate molecules, and the contact area between the candidate molecules and the solvent molecules, the electrostatic complementarity scoring applicability of each candidate molecule to the receptor protein is determined. Based on the applicability of electrostatic complementarity scoring between each candidate molecule and the receptor protein, at least one target candidate molecule suitable for electrostatic complementarity scoring is screened out, and the electrostatic complementarity scoring value between each target candidate molecule and the receptor protein is determined using the electrostatic complementarity scoring method. The binding activity of each target candidate molecule to the receptor protein is ranked based on the electrostatic complementarity score between each target candidate molecule and the receptor protein. The target protein surface region is the receptor protein surface region whose distance from any atom of the differential group is within a preset range. The determination of the target protein surface region corresponding to the differential group in each candidate molecule, based on the composite structure of each candidate molecule and the receptor protein, includes: Obtain the surface grid of the receptor protein; Based on the composite structure of the candidate molecule and the receptor protein, the distance between each surface lattice point of the receptor protein and any atom of the differential group in the candidate molecule is determined. The region composed of surface grid points whose distances from any atom of the differential group in the candidate molecule are within a preset range is taken as the target protein surface region corresponding to the differential group in the candidate molecule. The preset range is less than or equal to 3.5 angstroms; The determination of the electrostatic complementarity scoring applicability of each candidate molecule to the receptor protein is based on the polarity state of the differentially expressed groups in the candidate molecule, the polarity state of the target protein surface region corresponding to the differentially expressed groups in the candidate molecule, and the contact area between the candidate molecule and the solvent molecule. This includes: Based on the polarity state of the differential groups in the candidate molecules, determine whether the differential groups are polar groups; Based on the polarity state of the target protein surface region corresponding to the differentially expressed groups in the candidate molecules, determine whether the target protein surface region corresponding to the differentially expressed groups is a polar region; Based on the contact area between the candidate molecule and the solvent molecule, determine whether the interaction between the candidate molecule and the solvent molecule is weaker than the preset state. When the differential group is a polar group, the target protein surface region corresponding to the differential group is a polar region, and the interaction between the candidate molecule and the solvent molecule is weaker than the preset state, it is determined that the candidate molecule and the receptor protein are suitable for electrostatic complementary scoring. The contact area between the candidate molecule and the solvent molecule includes the first contact area between the candidate molecule and the solvent molecule in the recombination state and the second contact area between the candidate molecule and the solvent molecule in the non-recognition state. Determining whether the interaction between the candidate molecule and the solvent molecule is weaker than a preset state based on the contact area includes: Based on the molecular structure of the candidate molecule, the first contact area between the candidate molecule and the solvent molecule in the recombination state and the second contact area between the candidate molecule and the solvent molecule in the non-recognition state are determined. Based on the first contact area and the second contact area, determine whether the ratio of composite / non-composite solvent contact area of ​​the candidate molecule is less than a preset ratio. If the contact area ratio of the composite / non-composite solvent is determined to be less than a preset ratio, and the interaction between the candidate molecule and the solvent molecule is determined to be weaker than a preset state; and / or If the ratio of the contact area between the composite / non-composite solvent is determined to be not less than a preset ratio, then the interaction between the candidate molecule and the solvent molecule is determined to be not weaker than a preset state.

2. The method according to claim 1, characterized in that, The determination of whether a differentially differentiated group is a polar group based on the polarity state of the differentially differentiated groups in the candidate molecule includes: Based on the atom type of each atom in the differential group, determine whether there are polar atoms in the differential group; If a polar atom is found in the differentiating group, the differentiating group is determined to be a polar group; and / or If it is determined that there are no polar atoms in the differentiating group, the differentiating group is determined to be a nonpolar group.

3. The method according to claim 1, characterized in that, The determination of whether a target protein surface region corresponding to a differentially expressed group is a polar region, based on the polarity state of the target protein surface region corresponding to the differentially expressed group in the candidate molecule, includes: Based on the protein electrostatic potential at various points on the surface of the target protein, determine whether there are points on the surface of the target protein where the absolute value of the protein electrostatic potential is greater than a preset electrostatic potential, wherein the protein electrostatic potential is the electrostatic potential generated by the receptor protein at the current point. If a point is identified on the surface of the target protein where the absolute value of the protein's electrostatic potential is greater than a preset electrostatic potential, the target protein surface region is determined to be a polar region; and / or If there are no points on the surface of the target protein where the absolute value of the protein electrostatic potential is greater than the preset electrostatic potential, the surface region of the target protein is determined to be a nonpolar region.

4. The method according to claim 1, characterized in that, The determination of the electrostatic complementarity score between each target candidate molecule and the receptor protein using the electrostatic complementarity scoring method includes: Based on the molecular electrostatic potential and protein electrostatic potential at various points on the surface of the target candidate molecule, the electrostatic complementarity scoring method is used to determine the electrostatic complementarity score between the target candidate molecule and the receptor protein, wherein the molecular electrostatic potential is the electrostatic potential generated by the target candidate molecule at the current point, and the protein electrostatic potential is the electrostatic potential generated by the receptor protein at the current point.

5. A device for combining active sorting, characterized in that, include: A first processing module is configured to, in response to acquiring at least one differentially expressed group among multiple candidate molecules, determine a target protein surface region corresponding to the differentially expressed group in each candidate molecule based on the composite structure of each candidate molecule and the receptor protein; the target protein surface region is a receptor protein surface region whose distance from any atom of the differentially expressed group is within a preset range; the determination of the target protein surface region corresponding to the differentially expressed group in each candidate molecule based on the composite structure of each candidate molecule and the receptor protein includes: acquiring surface grid points of the receptor protein; determining the distance between each surface grid point of the receptor protein and any atom of the differentially expressed group in the candidate molecule based on the composite structure of the candidate molecule and the receptor protein; and taking the region composed of surface grid points whose distance from any atom of the differentially expressed group in the candidate molecule is within a preset range as the target protein surface region corresponding to the differentially expressed group in the candidate molecule; wherein, the preset range is less than or equal to 3.5 angstroms; The second processing module is used to determine the electrostatic complementarity scoring applicability of each candidate molecule to the receptor protein based on the polarity state of the differential groups in the candidate molecule, the polarity state of the target protein surface region corresponding to the differential groups in the candidate molecule, and the contact area between the candidate molecule and the solvent molecule. The determination of the electrostatic complementarity scoring applicability of each candidate molecule to the receptor protein is based on the polarity state of the differentially expressed groups in the candidate molecule, the polarity state of the target protein surface region corresponding to the differentially expressed groups in the candidate molecule, and the contact area between the candidate molecule and the solvent molecule. This includes: Based on the polarity state of the differential groups in the candidate molecules, determine whether the differential groups are polar groups; Based on the polarity state of the target protein surface region corresponding to the differentially expressed groups in the candidate molecules, determine whether the target protein surface region corresponding to the differentially expressed groups is a polar region; Based on the contact area between the candidate molecule and the solvent molecule, determine whether the interaction between the candidate molecule and the solvent molecule is weaker than the preset state. When the differential group is a polar group, the target protein surface region corresponding to the differential group is a polar region, and the interaction between the candidate molecule and the solvent molecule is weaker than the preset state, it is determined that the candidate molecule and the receptor protein are suitable for electrostatic complementary scoring. The contact area between the candidate molecule and the solvent molecule includes the first contact area between the candidate molecule and the solvent molecule in the recombination state and the second contact area between the candidate molecule and the solvent molecule in the non-recognition state. Determining whether the interaction between the candidate molecule and the solvent molecule is weaker than a preset state based on the contact area includes: Based on the molecular structure of the candidate molecule, the first contact area between the candidate molecule and the solvent molecule in the recombination state and the second contact area between the candidate molecule and the solvent molecule in the non-recognition state are determined. Based on the first contact area and the second contact area, determine whether the ratio of composite / non-composite solvent contact area of ​​the candidate molecule is less than a preset ratio. If the contact area ratio of the composite / non-composite solvent is determined to be less than a preset ratio, and the interaction between the candidate molecule and the solvent molecule is determined to be weaker than a preset state; and / or If the ratio of the contact area between the composite / non-composite solvent is determined to be not less than a preset ratio, then the interaction between the candidate molecule and the solvent molecule is determined to be not weaker than a preset state. The third processing module is used to screen out at least one target candidate molecule suitable for electrostatic complementarity scoring based on the applicability of electrostatic complementarity scoring between each candidate molecule and the receptor protein, and to determine the electrostatic complementarity score value between each target candidate molecule and the receptor protein using the electrostatic complementarity scoring method. The fourth processing module is used to rank the binding activity of each target candidate molecule to the receptor protein based on the electrostatic complementarity score between each target candidate molecule and the receptor protein.

6. An electronic device, characterized in that, include: A memory and a processor are communicatively connected, the memory storing computer instructions, and the processor executing the computer instructions to perform the combined activity sorting method according to any one of claims 1 to 4.

7. A computer-readable storage medium, characterized in that, The computer-readable storage medium stores computer instructions for causing the computer to perform the combination activity sorting method according to any one of claims 1 to 4.

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