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Finding potential inhibitors for Main protease (Mpro) of SARS-CoV-2 through virtual screening and MD simulation studies.

ABSTRACT: SARS-CoV-2 is a highly hazardous species that can infect people with Covid-19 disease, dramatically increasing mortality rates worldwide. Plenty of researches have been done to find drugs or inhibitors, with this study aiming to identify an inhibitor within the ChEMBL database using computational approaches. From the ChEMBL library, 19,43,048 compounds which are known type of small compounds and proteins were downloaded and docked with the Main protease (M^pro). After performing compound screening using Lipinski's rule, Qikprop analysis following with virtual Screening, Induced Fit Docking (IFD) and MM-GBSA analysis with the Glide and Prime modules of Schrödinger, the best complex was subjected to MD simulation with Desmond. According to the docking results, small protein 2,371,668 and compound 1,090,395 were docked with Main protease with -12.6, -12.0 kcal/mol dock score and interacted with the functional site residues His 41 and Cys 145, as well as the binding site residues Thr 26, Phe 140, Asn 142, Gly 143, Glu 166, and Gln 189. Complex structures were shown to be steadier by the MD simulation study because both the ligands heavy atoms and the protein Cα atoms' RMSD values fell within acceptable ranges. As a result, this research suggests that the molecule CHEMBL2371668 and the compound CHEMBL1090395 may inhibit the activity of Main protease, and the usefulness of these molecules will be examined further through experimental research.

SUBMITTER: Ahamed NA

PROVIDER: S-EPMC10663854 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Finding potential inhibitors for Main protease (Mpro) of SARS-CoV-2 through virtual screening and MD simulation studies.

Ahamed N Anis NA Arif Ibrahim A IA

Saudi journal of biological sciences 20231020 12

SARS-CoV-2 is a highly hazardous species that can infect people with Covid-19 disease, dramatically increasing mortality rates worldwide. Plenty of researches have been done to find drugs or inhibitors, with this study aiming to identify an inhibitor within the ChEMBL database using computational approaches. From the ChEMBL library, 19,43,048 compounds which are known type of small compounds and proteins were downloaded and docked with the Main protease (M<sup>pro</sup>). After performing compou ...[more]

PMID: 38020225

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Project description:The continued toll of COVID-19 has halted the smooth functioning of civilization on a global scale. With a limited understanding of all the essential components of viral machinery and the lack of structural information of this new virus, initial drug discovery efforts had limited success. The availability of high-resolution crystal structures of functionally essential SARS-CoV-2 proteins, including 3CLpro, supports the development of target-specific therapeutics. 3CLpro, the main protease responsible for the processing of viral polypeptide, plays a vital role in SARS-CoV-2 viral replication and translation and is an important target in other coronaviruses. Additionally, 3CLpro is the target of repurposed drugs, such as lopinavir and ritonavir. In this study, target proteins were retrieved from the protein data bank (PDB IDs: 6 M03, 6LU7, 2GZ7, 6 W63, 6SQS, 6YB7, and 6YVF) representing different open states of the main protease to accommodate macromolecular substrate. A hydroxyethylamine (HEA) library was constructed from harvested chemical structures from all the series being used in our laboratories for screening against malaria and Leishmania parasites. The database consisted of ∼1000 structure entries, of which 70% were new to ChemSpider at the time of screening. This in-house library was subjected to high throughput virtual screening (HTVS), followed by standard precision (SP) and then extra precision (XP) docking (Schrodinger LLC 2021). The ligand strain and complex energy of top hits were calculated by Molecular Mechanics Generalized Born Surface Area (MM/GBSA) method. Promising hit compounds (n = 40) specifically binding to 3CLpro with high energy and average MM/GBSA scores were then subjected to (100-ns) MD simulations. Using this sequential selection followed by an in-silico validation approach, we found a promising HEA-based compound (N,N'-((3S,3'S)-piperazine-1,4-diylbis(3-hydroxy-1-phenylbutane-4,2-diyl))bis(2-(5-methyl-1,3-dioxoisoindolin-2-yl)-3-phenylpropanamide)), which showed high in vitro antiviral activity against SARS-CoV-2. Further to reduce the size of the otherwise larger ligand, a pharmacophore-based predicted library of ∼42 derivatives was constructed, which were added to the previous compound library and rescreened virtually. Out of several hits from the predicted library, two compounds were synthesized, tested against SARS-CoV-2 culture, and found to have markedly improved antiviral activity.

Dataset Information

Finding potential inhibitors for Main protease (Mpro) of SARS-CoV-2 through virtual screening and MD simulation studies.

Publications

Finding potential inhibitors for Main protease (Mpro) of SARS-CoV-2 through virtual screening and MD simulation studies.

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