CN113274387A - Compound for preparing novel coronavirus inhibitor medicine - Google Patents

Compound for preparing novel coronavirus inhibitor medicine Download PDF

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CN113274387A
CN113274387A CN202110503308.8A CN202110503308A CN113274387A CN 113274387 A CN113274387 A CN 113274387A CN 202110503308 A CN202110503308 A CN 202110503308A CN 113274387 A CN113274387 A CN 113274387A
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compound
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novel coronavirus
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inhibitor
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毛辉
胡献跃
李群力
刘振香
费正新
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Jinhua Polytechnic
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Abstract

The invention belongs to the field of medicines, and particularly relates to a group of compounds for preparing novel coronavirus inhibitor medicines. Specifically, 12 compounds and/or any combination of 12 compounds, namely, ZINC96222420, ZINC96222315, ZINC253387805, ZINC970913, ZINC4090409, ZINC824654994, ZINC85593479, ZINC8791993, ZINC32949025, ZINC253387765, ZINC96296478 and ZINC 1073145. The invention also unexpectedly discovers that the binding conformation of the compound ZINC96222420 and SARS-CoV-2 main protease complex is highly stable, and the compound has great potential as a compound for preparing anti-new coronary pneumonia medicaments.

Description

Compound for preparing novel coronavirus inhibitor medicine
Technical Field
The invention belongs to the field of medicines, and particularly relates to a group of compounds for preparing novel coronavirus inhibitor medicines.
Background
At present, the development of efficient, inexpensive vaccines against novel coronaviruses remains a great challenge, in contrast to small molecule compounds which can more easily avoid polysaccharide coverage, thus providing an effective therapeutic approach.
The SARS-CoV-2 major protease (Mpro) is a class of cysteine hydrolases responsible for cleaving the translated protein precursors of the viral genome to achieve normal transcription and replication. The protein has highly conserved three-dimensional structure in various coronaviruses, and the characteristics of conservation and lack of human congeners provide a promising target for developing broad-spectrum anti-coronavirus therapeutic drugs. Hatada et al reported the interaction analysis of Mpro and its peptide-like inhibitor N3 complex based on the molecular orbital of the fragment, and found that His41, His163, His164 and Glu166 are the most important amino acid residues in the interaction of Mpro and inhibitor, and can form hydrogen bond with inhibitor molecule; tien revealed an important ligand binding mechanism of Mpro, demonstrating that ligand binding stability within the Mpro pocket can be significantly improved if the hydrophobic groups of the ligand occupy their so-called "anchor" sites.
The invention adopts a molecular docking and molecular dynamics method, unexpectedly virtually screens out a novel coronavirus main protease (Mpro) inhibitor from 20 ten thousand natural compounds in a ZINC15 database, and provides important reference for the development of novel anti-new-coronary-pneumonia small-molecule inhibitor medicines.
Disclosure of Invention
In order to solve the problems, the invention discloses a group of compounds used for preparing novel coronavirus inhibitor medicines, in particular 12 compounds and/or any combination mode of the 12 compounds, namely ZINC96222420, ZINC96222315, ZINC253387805, ZINC970913, ZINC4090409, ZINC824654994, ZINC85593479, ZINC8791993, ZINC32949025, ZINC253387765, ZINC96296478 and ZINC 1073145.
On the other hand, the invention also discloses the application of the 12 compounds and/or any combination mode of the 12 compounds in the preparation of novel coronavirus inhibitor medicaments.
Specifically, the chemical structures of the above 12 compounds are specifically as follows:
Figure BDA0003057269030000021
preferably, the invention discloses a group of compounds used for preparing novel coronavirus inhibitor medicines, in particular 4 compounds and/or any combination mode of the 4 compounds, namely ZINC96222420, ZINC96222315, ZINC253387805 and ZINC 4090409.
More preferably, the invention discloses a compound used for preparing a novel coronavirus inhibitor drug, in particular to ZINC 96222420.
The invention has the beneficial effects that:
(1) the invention discloses a compound used for preparing a novel coronavirus inhibitor medicine 12, and provides important reference for development of a novel anti-new-coronary-pneumonia small-molecule inhibitor medicine.
(2) The invention unexpectedly discovers that the binding conformation of the compound ZINC96222420 and SARS-CoV-2 main protease complex is highly stable, and the compound has the potential of being used as a compound for preparing anti-new coronary pneumonia medicines.
Drawings
FIG. 1 is a chemical structural diagram of 12 compounds according to the present invention.
FIG. 2 is a diagram showing the molecular docking of 4 compounds of example 5 with a target protein, wherein 2A corresponds to the compound ZINC96222420, 2B corresponds to ZINC96222315, 2C corresponds to ZINC253387805, and 2D corresponds to ZINC4090409, wherein (1) is an electrostatic potential surface and (2) is an electrostatic potential surface.
FIG. 3 is a graph of RMSD results for protein and ligand scaffolds during the simulation of example 6.
FIG. 4 is a graph of the results of the interaction between a compound and Mpro during the MD simulation of example 6.
FIG. 5 is a graph showing the results of radius gyration of the protein of example 6.
FIG. 6 is a graph of overlay comparison results for the pre-simulation (dark gray) and post-simulation (light gray) systems of example 6.
FIG. 7 is a heat map of hydrogen bonding of ligands to receptors during the MD simulation of example 6.
Detailed Description
The present invention will be described in further detail with reference to the following detailed description and accompanying drawings. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
The virtual screening software of the invention selects Maestro (software from Schrodinger 2020-2); the protein crystal structures were obtained from the PDB database (https:// www.rcsb.org); the structure of the compound is from natural small molecular compounds of a ZINC compound library, and the total number of the natural small molecular compounds is 20 ten thousand.
EXAMPLE 1 treatment of the Crystal Structure of the SARS-Cov-2-Mpro protein
The three-dimensional crystal structure of the Mpro protein was obtained from PDB data searchable and downloadable, with PDB code of 6LU7 and crystal structure resolution of
Figure BDA0003057269030000041
The 6LU7 structure is modified chemically by Protein Preparation Wizard of Maestro software, hydrogenated,and (3) processing metal ions, filling up the missing atoms and amino acid residues, deleting redundant molecules and the like, and then performing energy optimization on the protein under the condition of an OPLS (optical phase shift laser) force field to finally serve as a receptor for molecular docking.
EXAMPLE 2 drug binding site
6LU7 is a complex crystal structure of COVID-19 virus Mpro with compound N3, the docking target is based on the active pocket defined by the proligand inhibitor N3 in this crystal complex, and the docking lattice is produced by Receptor identification Generation in the Maestro software.
Example 3 Compound Structure treatment, molecular docking and molecular dynamics simulation
The natural compound small molecules provided by the ZINC database amount to 20 million. And (3) optimizing the compound molecules by using a 'Ligprep' module in software.
6LU7 is used as a rigid receptor, and optimized compound molecules are used as flexible ligands to carry out semi-flexible docking. The method adopts a 'Ligand Docking' module to carry out high-throughput virtual screening, takes a Docking score as a screening condition, and constructs a compound of SARS-Cov-2-Mpro protein and a candidate drug for molecular dynamics simulation.
Molecular dynamics simulations were performed by a pmemd. cuda module in AMBER software package that could perform GPU acceleration. The protonation state of the titratable residues of the protein was predicted by H + + at pH 7.0. Of these, His41 and His80 were N.delta.protonated, while His64, His163, His164, His172 and His246 were N.epsilon.protonated. Proteins were hydrotreated using the "reduce" program from AmberTools18 and then visually inspected by the PyMOL program. The electrostatic potential of the substrate was calculated at HF/6-31G theory level, the RESP charge was calculated using Multiwfn 3.7, and the atomic type and parameters of all substrates were obtained by ACPYPE by adding a gaff2 force field to the small molecule substrate. The protein-small molecule complex structure is then immersed in a TIP3P water box such that its edges are at least the distance of any protein atom
Figure BDA0003057269030000051
And adding a counter ion (Na)+And Cl-) The charge is neutralized.Protein and ion parameters are described by the ff14SB force field, and the cutoff values for calculation of Lennard-Jones and Coulomb interactions, calculation of long range electrostatic interactions using the PME method, and confinement of hydrogen-containing bonds using the SHAKE algorithm are all set to values
Figure BDA0003057269030000052
To eliminate poor contact, three stages of energy minimization are performed to optimize the geometry. First, the entire protein, cofactor and substrate are subjected to
Figure BDA0003057269030000053
Force constant constraints were maintained for 5000 cycles (2500 steps steepest descent method and 2500 steps conjugate gradient method). Then, the skeleton atoms of the protein are subjected to
Figure BDA0003057269030000054
For the force constant constraint, 5000-step energy minimization (2500-step steepest descent method and 2500-step conjugate gradient method) is performed. Finally, the entire system performs 10000 steps of energy minimization (5000 steps of steepest descent method and 5000 steps of conjugate gradient method) without setting any constraint. After optimization of the structure, 100ps was heated to 300K at constant volume and the temperature was adjusted using Langevin thermo stat with a coupling time constant of 1.0ps
Figure BDA0003057269030000055
To restrict enzymes, cofactors and substrates. Use of
Figure BDA0003057269030000061
The position constraint was performed to balance the density at constant pressure for 500ps, followed by an unconstrained NPT simulation of 1ns in which both the temperature coupling and pressure relaxation times were set to 5 ps. After 300K equilibration, a 50ns MD simulation was performed in the NPT ensemble, where the temperature was maintained using Langevin thermo stat and the pressure was controlled at 1.0atm using Monte Carlo barostat. The simulation time step is 2fs, saving the trace every 10 ps. MD traces were analyzed using the CPPTRAJ program and post-processed,visual inspection is performed using VMD.
Example 4 Combined free energy calculation
Combining free energy is calculated and decomposed by using an MM/GBSA method on MD simulation data (300 frames) in 20-50ns in a system equilibrium state, and the decomposition process consists of four energy items: Δ Gbind ═ Δ Evdw + Δ Eele + Δ Gpol + Δ Gnopol, Δ Evdw denotes non-bond van der waals interactions, Δ Evdw denotes electrostatic interactions, and Δ Gpol and Δ Gnopol denote polar and non-polar interactions, respectively, which constitute solvation free energy. Igb is set to 5 in the input file, and the other parameters are default values. MM/GBSA calculations were performed using mmpbsa. py program in AmberTools 18.
Example 5 molecular docking results
High-throughput screening is carried out on 20 ten thousand ZINC small molecule compound libraries, 12 compounds with the highest docking fraction are finally screened, the screening result is shown in table 1, and the structure of the compound is shown in table 1. The 4 compounds, 4 of which were ZINC96222420, ZINC96222315, ZINC253387805 and ZINC4090409, were further analyzed by comprehensive evaluation.
TABLE 1
Tab.1 Virtual screening results of drug candidates
Figure BDA0003057269030000071
The docking scheme of the ZINC96222420 small molecule and the target protein molecule is shown in FIG. 2A. The knock score of this compound was-8.963 kcal/mol. A small molecule phenol fragment extends into an active cavity consisting of Met49, Pro52, Asp187 and Arg 188; the nitrogen atom on the six-membered nitrogen heterocycle and the imino hydrogen on the five-membered nitrogen heterocycle can form a hydrogen bond with Glu166, and the bond lengths are respectively
Figure BDA0003057269030000072
And
Figure BDA0003057269030000073
hydrogen of hydroxyl on a benzene ring adjacent to the oxygen-containing five-membered ring can form a hydrogen bond with Leu141, and the bond length is
Figure BDA0003057269030000074
The diagram of the alignment of the ZINC96222315 small molecule and the target protein molecule is shown in FIG. 2B. The knock score of this compound was-8.807 kcal/mol. The hydrogen atom on the peptide bond forms a hydrogen bond with His164, and the bond length is
Figure BDA0003057269030000081
The imino hydrogen atom on the six-membered nitrogen heterocycle forms a hydrogen bond with Leu141, and the bond length is
Figure BDA0003057269030000082
The carbonyl oxygen atom on the six-membered nitrogen heterocycle forms a hydrogen bond with Cys145, and the bond length is
Figure BDA0003057269030000083
The alignment of the small molecule and the target protein molecule of ZINC253387805 is shown in FIG. 2C. The mark value of the compound packaging score is-8.756 kcal/mol, in the structure, imino hydrogen atom on glycine, oxygen atom on asparagine main chain and imino hydrogen atom on imidazole group of histidine side chain all form hydrogen bond with Glu166, and the bond length is respectively
Figure BDA0003057269030000084
And
Figure BDA0003057269030000085
the imino hydrogen atom on leucine and the imino hydrogen atom on asparagine side chain both form hydrogen bonds with Gln189, and the bond lengths are respectively
Figure BDA0003057269030000086
And
Figure BDA0003057269030000087
the imino hydrogen atom on asparagine forms a hydrogen bond with His164, the bond length is
Figure BDA0003057269030000088
The oxygen atom near the benzene ring forms a hydrogen bond with Gly143, and the bond length is
Figure BDA0003057269030000089
The peptide bond oxygen atom near the benzene ring forms a hydrogen bond with Hie41, and the bond length is
Figure BDA00030572690300000810
The molecular docking diagram of the ZINC4090409 small molecule and the target protein is shown in FIG. 2D. The knock score of this compound was-8.676 kcal/mol. The peptide bond oxygen atom of the six-membered nitrogen heterocycle forms a hydrogen bond with Glu166, and the bond length is
Figure BDA00030572690300000811
The imino hydrogen atom on phenylalanine forms a hydrogen bond with Gln189, the bond length being
Figure BDA00030572690300000812
The imino hydrogen atom on alanine forms a hydrogen bond with His164, the bond length being
Figure BDA00030572690300000813
The oxygen atom of alanine forms a hydrogen bond with Cys145, the bond length being
Figure BDA00030572690300000814
The small molecular terminal oxygen atom and Gly143 form a hydrogen bond with the bond length of
Figure BDA00030572690300000815
The benzene ring on phenylalanine forms stable pi-pi stacking with Hie 41. The hydrogen bonds are indicated by the yellow dotted line, with distances indicated, and pi-pi stacking is indicated by the blue dotted line
Example 6 molecular dynamics simulation
Molecular dynamics simulations were performed on the highest scoring ZINC96222420 small molecule among the 4 compounds in example 5. To ensure kinetic stability and sampling rationality, the RMSD (Root-mean-square resolution) values of the protein backbone atoms were calculated based on the crystal structure (fig. 3). If the global RMSD valueIs less than
Figure BDA0003057269030000091
It indicates that the system is in equilibrium. RMSD shows that the complex reaches equilibrium around 5ns and reaches equilibrium
Figure BDA0003057269030000092
Left and right stability. The RMSD was low during the simulation, indicating that the formed complex was stable. The ligand RMSD was also stable throughout the simulation with little fluctuation as found by the protein scaffold RMSD. The mean conformation (fig. 4) indicates that the ligand molecule binds to the receptor in a manner consistent with the initial state during the simulation.
Another characterization feature of the stability of the molecular dynamics system is the radius of gyration (Rg) of the protein, the range of which reflects the degree of compaction of the protein, with larger values leading to more relaxation of the protein. In the present invention, the total Rg value and Rg values for each dimension are shown in fig. 5. Wherein the total Rg remains essentially unchanged, indicating that the protein remains in a stable and dense state throughout the simulation. While the final conformation of the complex overlaps the initial conformation (FIG. 6) indicating that there is little conformational deviation of both the protein and the inhibitor. These results show that the complex system remains stable throughout and can be further analyzed. The thermal map of intermolecular hydrogen bonding between receptor and ligand is shown in fig. 7, and during the kinetic simulation, the system maintained on average >2 intermolecular hydrogen bonds, consistent with the docking results.
Example 7 binding free energy analysis
The contribution of the MM-GBSA binding free energy of the ZINC96222420 to the target protein is listed in table 2, the total binding energy of the complex is-30.2352 kcal/mol, the low binding energy further defines the stability of the complex. Wherein the net gas phase energy is-59.1985 kcal/mol. For this energy, van der Waals plays a powerful role (-35.5349 kcal/mol). The effect of electrostatic energy in the binding is relatively small (-23.6636 kcal/mol). The total solvation energy of MM-GBSA is 28.9633 kcal/mol. In addition, the present application focuses on the contribution of amino acids that interact with inhibitors in docking models, in combination with the breakdown of the binding energy to specific amino acids. The binding free energy of the hot spot receptor residues (binding energy contribution greater than 0.5kcal/mol) interacting with the inhibitor during the molecular dynamics simulation is shown below: met165 (-2.5023kcal/mol), Glu166(-2.4046kcal/mol), Asp187(-1.9558 kcal/mol), Met49(-1.2253kcal/mol), Gln192(-0.9701kcal/mol), Arg188 (-0.9678kcal/mol), Gln189(-0.7984kcal/mol), His41(-0.7678 kcal/mol), Cys145(-0.7175kcal/mol), Ser144(-0.6901kcal/mol), Asn142(-0.6760kcal/mol), which have a high degree of agreement with the docking model, indicating that the model has better reliability.
TABLE 2
Figure BDA0003057269030000111
Figure BDA0003057269030000121
In conclusion, the Mpro protease is the main functional protein of coronaviruses such as SARS-CoV and SARS-CoV-2. The application adopts a molecular docking and molecular dynamics method, unexpectedly, a novel coronavirus main protease (Mpro) inhibitor is virtually screened from 20 ten thousand natural compounds in a ZINC15 database, and the novel coronavirus main protease (Mpro) inhibitor can be used for preparing a compound serving as a novel coronavirus inhibitor drug. The molecular dynamics simulation of 50ns aqueous solution proves that the binding conformation of the ZINC96222420 compound and the SARS-CoV-2 main protease complex is highly stable. The binding free energy calculated by the MM-GBSA method also confirms the stability of the ZINC96222420-Mpro complex. Based on these validation results, the present application discloses that the shuffled compounds have the potential to be developed into novel anti-neocoronary pneumonia drug molecules, in particular the compound ZINC 96222420.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.

Claims (5)

1. A group of compounds for preparing novel coronavirus inhibitor medicaments is characterized by comprising 12 compounds and/or any combination of 12 compounds, namely ZINC96222420, ZINC96222315, ZINC253387805, ZINC970913, ZINC4090409, ZINC824654994, ZINC85593479, ZINC8791993, ZINC32949025, ZINC253387765, ZINC96296478 and ZINC 1073145.
2. The compound of claim 1, wherein the chemical structures of the 12 compounds are specifically as follows:
Figure FDA0003057269020000011
3. use of a compound according to claim 1 for the preparation of a novel coronavirus inhibitor medicament.
4. A group of compounds for preparing novel coronavirus inhibitor medicines is characterized by specifically comprising 4 compounds and/or any combination mode of the 4 compounds, namely ZINC96222420, ZINC96222315, ZINC253387805 and ZINC 4090409.
5. A compound used for preparing novel coronavirus inhibitor medicine is specifically ZINC 96222420.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111809246A (en) * 2020-07-23 2020-10-23 金华职业技术学院 Method for screening small-molecule peptide mimetic inhibitor and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111809246A (en) * 2020-07-23 2020-10-23 金华职业技术学院 Method for screening small-molecule peptide mimetic inhibitor and application thereof

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* Cited by examiner, † Cited by third party
Title
ZINK: "zink化合物", 《ZINK 数据库》 *

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