A molecular docking method and system based on conformation-dependent charge

Abstract

The present invention discloses a molecular docking method and system based on conformation-dependent charge, comprising: performing a conformational search on a structurally optimized small molecule ligand to obtain a small molecule conformation; calculating the RESP charge of the stable conformation in a vacuum after structural optimization of the small molecule conformation; assigning the RESP charge to the small molecule conformation obtained after structural optimization to obtain a ligand charge; performing molecular docking on a protein-ligand complex under an existing force field mode, and using the obtained ligand charge in molecular docking. By combining a conformational search for drug small molecules with a charge fitting method, multiple sets of RESP charge parameters are obtained for each drug molecule based on its different conformations, thereby improving the accuracy of molecular docking.

Description

Technical Field

[0001] The present invention relates to the technical field of drug molecule docking, and in particular to a molecular docking method and system based on conformation-dependent charge. Background Art

[0002] The statements in this section merely provide background information related to the present invention and do not necessarily constitute prior art.

[0003] Molecular docking is commonly used to study intermolecular interactions during drug development. It is a theoretical simulation method for predicting receptor-ligand binding patterns and affinities. Traditional molecular docking typically uses empirical force fields or scoring functions to calculate ligand-receptor interactions. The corresponding parameters are derived from the default force field, resulting in fast calculation speeds and the ability to rapidly screen databases of millions of small molecules.

[0004] The accuracy of molecular docking is crucial for structure-based virtual screening. Structure-based virtual screening utilizes molecular docking techniques to predict the binding modes of small molecules in a compound database. Binding energies are calculated based on a scoring function derived from a molecular force field, ultimately resulting in a ranking of compounds. The higher the accuracy of molecular docking, the higher the ranking of active compounds, making them more likely to be selected through virtual screening and subsequently proceed to bioactivity testing. Therefore, the performance of molecular docking is significantly influenced by the force field, and electrostatic interactions play a crucial role in receptor-ligand binding.

[0005] The invention patent with patent number CN111199771A, based on traditional molecular docking, identifies the polarizable bonds contained in the ligand and updates the charge based on the protein environment in which the ligand is located, effectively improving the accuracy of molecular docking.

[0006] Using an appropriate charge model is crucial for accurate molecular docking. Restrained ElectroStatic Potential (RESP) charges are a type of atomic charge suitable for flexible small molecules in molecular simulations. However, molecular docking typically uses a fixed force field to assign charges to ligand small molecules. This ignores the effects of conformational changes on charge distribution, resulting in a loss of accuracy in the calculation of receptor-ligand interactions. Summary of the Invention

[0007] In order to solve the above problems, the present invention proposes a molecular docking method and system based on conformation-dependent charge. Through the method of drug small molecule conformation search combined with charge fitting, multiple sets of RESP charge parameters are obtained for each drug molecule according to its different conformations to improve the accuracy of molecular docking.

[0008] In order to achieve the above object, the present invention adopts the following technical solutions:

[0009] In a first aspect, the present invention provides a molecular docking method based on conformation-dependent charge, comprising:

[0010] After the structure of the small molecule ligand is optimized, a conformational search is performed to obtain the small molecule conformation;

[0011] Calculate the RESP charge of small molecule conformations;

[0012] Assign the RESP charge to the structurally optimized small molecule conformation to obtain the ligand charge;

[0013] Ligand charge was used for molecular docking of receptor-ligand complexes.

[0014] As an optional embodiment, the two-dimensional structure of the small molecule ligand is converted into a three-dimensional structure and then subjected to structural optimization.

[0015] As an optional implementation method, the three-dimensional structure of the small molecule ligand is optimized using quantum chemical methods, and frequency analysis is performed to obtain a low-energy three-dimensional conformation of the small molecule ligand.

[0016] As an optional implementation, a conformational search is performed on the low-energy three-dimensional conformations of the small molecule ligand, and the top N small molecule conformations obtained by the conformational search are retained.

[0017] As an optional embodiment, quantum chemical methods are used to optimize the structure of small molecule conformations.

[0018] As an alternative embodiment, the RESP charge in vacuum is calculated for the small molecule conformation after structural optimization.

[0019] As an optional embodiment, each small molecule ligand has multiple sets of charge distributions depending on its conformation.

[0020] In a second aspect, the present invention provides a molecular docking system based on conformation-dependent charge, comprising:

[0021] The conformation search module is configured to perform conformation search on the small molecule ligand after structural optimization to obtain the small molecule conformation;

[0022] a charge calculation module configured to calculate RESP charges of small molecule conformations;

[0023] An assignment module is configured to assign RESP charges to the structurally optimized small molecule conformation to obtain ligand charges;

[0024] The docking module is configured to perform molecular docking of receptor-ligand complexes using ligand charges.

[0025] In a third aspect, the present invention provides an electronic device comprising a memory and a processor, and computer instructions stored in the memory and executed on the processor, wherein the computer instructions, when executed by the processor, perform the method described in the first aspect.

[0026] In a fourth aspect, the present invention provides a computer-readable storage medium for storing computer instructions, wherein when the computer instructions are executed by a processor, the method described in the first aspect is performed.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The present invention proposes a molecular docking method and system based on conformation-dependent charge. By searching the conformation of small drug molecules and combining them with a charge fitting method, multiple sets of RESP charge parameters are obtained for each drug molecule according to its different conformations, thereby improving the accuracy of molecular docking.

[0029] The docking method based on conformation-dependent charge can not only improve the accuracy of molecular docking, but also improve the enrichment ability of docking scoring, which is conducive to ranking active compounds at the front in virtual screening and improving the hit rate of virtual screening.

[0030] Advantages of additional aspects of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The accompanying drawings, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0032] Figure 1 Schematic diagram of the molecular docking method based on conformation-dependent charge provided in Example 1 of the present invention;

[0033] Figure 2(a)-2(b) This is a schematic diagram of the docking structure of upadacitinib and JAK1 kinase provided in Example 1 of the present invention and the reported structure. DETAILED DESCRIPTION

[0034] The present invention will be further described below with reference to the accompanying drawings and embodiments.

[0035] It should be noted that the following detailed descriptions are exemplary and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0036] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that the terms "including" and "having" and any variations thereof are intended to cover non-exclusive inclusions. For example, a process, method, system, product or device comprising a series of steps or units is not necessarily limited to those steps or units clearly listed, but may include other steps or units that are not clearly listed or inherent to these processes, methods, products or devices.

[0037] In the absence of conflict, the embodiments of the present invention and the features thereof may be combined with each other.

[0038] Example 1

[0039] Traditional molecular docking methods use fixed force field ligand charges for small molecule ligands, ignoring the impact of conformational changes on charge distribution and compromising the accuracy of receptor-ligand interactions. Therefore, this example builds on traditional molecular docking and uses quantum chemical calculations to perform charge fitting based on the different conformations of small molecule ligands. Multiple sets of RESP charge parameters are generated for each drug molecule based on its different conformations, fully accounting for the impact of conformational changes on charge distribution.

[0040] like Figure 1 As shown, this embodiment proposes a molecular docking method based on conformation-dependent charge, comprising:

[0041] After the structure of the small molecule ligand is optimized, a conformational search is performed to obtain the small molecule conformation;

[0042] Calculate the RESP charge of small molecule conformations;

[0043] Assign the RESP charge to the structurally optimized small molecule conformation to obtain the ligand charge;

[0044] Ligand charge was used for molecular docking of receptor-ligand complexes.

[0045] In this embodiment, the two-dimensional structure of the small molecule ligand is converted into a three-dimensional structure, and the structure is optimized using quantum chemical methods to obtain a low-energy three-dimensional conformation; a conformational search is performed on the low-energy three-dimensional conformation of the small molecule ligand, and the small molecule conformation obtained by the conformational search is retained;

[0046] As an optional implementation method, the first 30 conformations obtained by the conformational search are retained;

[0047] Furthermore, in order to achieve higher accuracy and efficiency, the top 10 conformations obtained by the conformational search are retained.

[0048] In this embodiment, the small molecule conformation obtained by the conformational search is subjected to structural optimization using quantum chemical methods to obtain the local minimum energy geometric configuration, and then the RESP charge of the conformation in vacuum is calculated.

[0049] In this embodiment, the charge is updated by assigning the calculated RESP charge to the small molecule conformation after conformational search and structure optimization to obtain the ligand charge.

[0050] In this embodiment, for each receptor-ligand complex, such as a protein-ligand complex, when molecular docking is performed in the existing force field mode, the ligand charge is used to obtain the binding mode structure; the accuracy of molecular docking is improved based on the RESP charge parameters of different conformations.

[0051] In this embodiment, taking the first 10 conformations as an example (the same applies to the first 30 conformations), the molecular docking method based on conformation-dependent charge specifically includes:

[0052] 1) According to the two-dimensional structure of small molecule ligands, Draw its three-dimensional structure, and use quantum chemical calculation software (Gaussian16) to optimize and perform frequency analysis to obtain the low-energy geometric configuration of the small molecule ligand.

[0053] 2) Use the small molecule ligand optimized by Gaussian16 The ConformationalSearch tool was used to perform conformational search, and the top 10 small molecule conformations obtained by the conformational search were retained.

[0054] 3) The top 10 small molecule conformations obtained by the conformational search were optimized using Gaussian16 and subjected to frequency analysis. All *.log files after Gaussian16 optimization were converted into *.mol2 format files using Open Babel and then imported into In the software, adjust the structure and then Export *mol2 format files.

[0055] 4) Update the charges. Generate *.fchk files from the *.chk files of all 10 conformations obtained after Gaussian 16 optimization. Calculate the RESP charges of all *.fchk files using Multiwfn 3.8 to obtain *.chg files. Round off the charges in the *.chg files to five decimal places (truncate the first five digits, not round them off) and assign these values ​​to the *mol2 files of the 10 conformations obtained in step 3.

[0056] 5) For each protein-ligand complex, use Molecular docking was performed in the OPLS_2005 force field mode, forcing the use of the conformation-dependent charges calculated in step 4. Each small molecule ligand has multiple sets of charge distributions depending on its conformation, which improves the accuracy of molecular docking.

[0057] like Figure 2(a)-2(b) As shown, using the conformation-dependent charge docking method, upadacitinib achieved a higher docking score for JAK1 kinase (docking score = -9.662 kcal / mol) than for JAK2 (docking score = -9.066 kcal / mol) and TYK2 (docking score = -5.921 kcal / mol), consistent with the fact that this drug is a known highly selective JAK1 kinase inhibitor. Furthermore, the docked structure of upadacitinib and JAK1 kinase obtained using the method of this example is similar to previously reported structures, further demonstrating that conformation-dependent charge-based docking can improve the accuracy of molecular docking.

[0058] In another validation case, RNA-dependent RNA polymerase (RdRP) is a class of polymerases that synthesizes complementary RNA chains using single-stranded RNA as a template. It is a core component of coronavirus replication and is considered one of the two major targets of SARS-CoV-2. The development of new drugs for SARS-CoV-2 is a time-consuming, labor-intensive, high-investment, and high-risk process that cannot meet the needs of clinical treatment in the short term. To discover potential RdRP inhibitors from existing nucleotide drugs, a charge-dependent docking method was used to predict the antiviral activity of existing nucleotide drugs.

[0059] As shown in Table 1-2, the conformation-dependent charge-based docking method can effectively improve the enrichment ability of the docking score for active compounds. Most compounds with antiviral activity at the cellular level are enriched to the top (top 30%). This shows that the conformation-dependent charge-based docking method can not only improve the accuracy of molecular docking, but also improve the enrichment ability of the docking score, which is beneficial for ranking active compounds at the top in virtual screening and improving the hit rate of virtual screening.

[0060] Table 1 Antiviral activity and molecular docking scores of some nucleoside drugs when the first 30 conformations were taken

[0061]

[0062] Table 2 Antiviral activity and molecular docking scores of some nucleoside drugs when the first 10 conformations are adopted

[0063]

[0064] Example 2

[0065] This embodiment provides a molecular docking system based on conformation-dependent charge, comprising:

[0066] The conformation search module is configured to perform conformation search on the small molecule ligand after structural optimization to obtain the small molecule conformation;

[0067] a charge calculation module configured to calculate RESP charges of small molecule conformations;

[0068] An assignment module is configured to assign RESP charges to the structurally optimized small molecule conformation to obtain ligand charges;

[0069] The docking module is configured to perform molecular docking of receptor-ligand complexes using ligand charges.

[0070] It should be noted that the above modules correspond to the steps described in Example 1, and the examples and application scenarios implemented by the above modules and the corresponding steps are the same, but are not limited to the contents disclosed in the above Example 1. It should be noted that the above modules, as part of the system, can be executed in a computer system such as a set of computer-executable instructions.

[0071] In further embodiments, there is also provided:

[0072] An electronic device includes a memory and a processor, and computer instructions stored in the memory and executed by the processor, wherein when the computer instructions are executed by the processor, the method described in Example 1 is performed. For the sake of brevity, no further details are given here.

[0073] It should be understood that in this embodiment, the processor may be a central processing unit (CPU), or may be other general-purpose processors, digital signal processors (DSP), application-specific integrated circuits (ASIC), off-the-shelf field-programmable gate arrays (FPGA), or other programmable logic devices, discrete gate or transistor logic devices, discrete hardware components, etc. The general-purpose processor may be a microprocessor or any conventional processor, etc.

[0074] The memory may include a read-only memory and a random access memory, and provides instructions and data to the processor. A portion of the memory may also include a non-volatile random access memory. For example, the memory may also store information about the device type.

[0075] A computer-readable storage medium is used to store computer instructions, and when the computer instructions are executed by a processor, the method described in Example 1 is performed.

[0076] The method in Example 1 can be directly implemented as a hardware processor, or can be implemented using a combination of hardware and software modules in the processor. The software module can be located in a storage medium mature in the art, such as random access memory, flash memory, read-only memory, programmable read-only memory, electrically erasable programmable memory, registers, etc. The storage medium is located in the memory, and the processor reads the information in the memory and, in conjunction with its hardware, completes the steps of the above method. To avoid repetition, it will not be described in detail here.

[0077] Those skilled in the art will appreciate that the units, i.e., algorithm steps, of the various examples described in conjunction with this embodiment can be implemented using electronic hardware or a combination of computer software and electronic hardware. Whether these functions are performed in hardware or software depends on the specific application and design constraints of the technical solution. Professionals and technicians may use different methods to implement the described functions for each specific application, but such implementation should not be considered beyond the scope of this application.

[0078] Although the above describes the specific embodiments of the present invention in conjunction with the accompanying drawings, it is not intended to limit the scope of protection of the present invention. Those skilled in the art should understand that various modifications or variations that can be made by those skilled in the art on the basis of the technical solution of the present invention without any creative work are still within the scope of protection of the present invention.

Claims

1. A molecular docking method based on conformation-dependent charge, characterized in that: include: After the structure of the small molecule ligand is optimized, a conformational search is performed to obtain the small molecule conformation; Calculate the RESP charge of small molecule conformations; Assign the RESP charge to the structurally optimized small molecule conformation to obtain the ligand charge; Ligand charge was used for molecular docking of receptor-ligand complexes.

2. A molecular docking method based on conformation-dependent charge according to claim 1, characterized in that: The two-dimensional structure of the small molecule ligand is converted into a three-dimensional structure and then the structure is optimized.

3. A molecular docking method based on conformation-dependent charge according to claim 2, characterized in that: The three-dimensional structure of the small molecule ligand is optimized using quantum chemical methods, and frequency analysis is performed to obtain the low-energy three-dimensional conformation of the small molecule ligand.

4. A molecular docking method based on conformation-dependent charge according to claim 3, characterized in that: Perform conformational search on the low-energy three-dimensional conformations of the small molecule ligand and retain the top N small molecule conformations obtained by the conformational search.

5. The molecular docking method based on conformation-dependent charge according to claim 1, wherein: Quantum chemical methods are used to optimize the structure of small molecules.

6. A molecular docking method based on conformation-dependent charge according to claim 1, characterized in that: After structural optimization of the small molecule conformation, the RESP charge in vacuum is calculated.

7. The molecular docking method based on conformation-dependent charge according to claim 1, characterized in that: Each small molecule ligand has multiple sets of charge distributions depending on its conformation.

8. A molecular docking system based on conformation-dependent charge, characterized in that: include: The conformation search module is configured to perform conformation search on the small molecule ligand after structural optimization to obtain the small molecule conformation; a charge calculation module configured to calculate RESP charges of small molecule conformations; An assignment module is configured to assign RESP charges to the structurally optimized small molecule conformation to obtain ligand charges; The docking module is configured to perform molecular docking of receptor-ligand complexes using ligand charges.

9. An electronic device, characterized in that: The method comprises a memory and a processor, and computer instructions stored in the memory and executed on the processor, wherein when the computer instructions are executed by the processor, the method according to any one of claims 1 to 7 is completed.

10. A computer-readable storage medium, characterized in that Used to store computer instructions, which, when executed by a processor, complete the method according to any one of claims 1 to 7.

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