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Synthesis and Identification of Novel Potential Molecules Against COVID-19 Main Protease Through Structure-Guided Virtual Screening Approach.

ABSTRACT: The novel coronavirus disease that arises in the end of 2019 (COVID-19) in Wuhan, China, has rapidly spread over the globe and was considered as a world pandemic. Currently, various antiviral therapies or vaccines are available, and many researches are ongoing for further treatments. Targeting the coronavirus' main protease (key enzyme: 3CLpro) is growing in importance in anti-SARS-CoV-2 drug discovery process. The present study aims at predicting the antiviral activity of two novel compounds using in silico approaches that might become potential leads against SARS-CoV-2. The 3D structures of the new compounds are elucidated by single-crystal X-ray techniques. The interactions between different units of 4 and 5 were emphasized by analyzing their corresponding Hirshfeld surfaces and ESP plots. NBO and FMO analyses were investigated as well. Molecular docking combined with molecular dynamics simulations (MDs) was performed to investigate the binding modes and molecular interactions of 4 and 5 with the amino acids of coronavirus main protease (6LU7) protein. The best docking scores were obtained for both ligands through the major binding interactions via hydrogen/hydrophobic bonds with the key amino acids in the active site: HIS41, CYS145, MET49, MET165, HIS172, and GLU166 amino acids. A MD simulation study was also performed for 100 ns to validate the stability behavior of the main protease 3CLpro-ligand complexes. The MD simulation study successfully confirmed the stability of the ligands in the binding site as potent anti-SARS-CoV-2 (COVID-19) inhibitors. Additionally, MMPBSA energy of both docked complexes was determined as a validation assay of docking and MD simulations to validate compound conformation and interaction stability with 3CLpro. The synthesized compounds might be helpful in the fight against COVID-19 prior to biological activity confirmation in vitro and in vivo.

SUBMITTER: El Bakri Y

PROVIDER: S-EPMC8319192 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The COVID-19 disease is caused by a new strain of the coronavirus family (SARS-CoV-2), and it has affected at present millions of people all over the world. The indispensable role of the main protease (Mpro) in viral replication and gene expression makes this enzyme an attractive drug target. Therefore, inhibition of SARS-CoV-2 Mpro as a proposition to halt virus ingression is being pursued by scientists globally. Here we carried out a study with two objectives: the first being to perform comparative protein sequence and 3D structural analysis to understand the effect of 12 point mutations on the active site. Among these, two mutations, viz., Ser46 and Phe134, were found to cause a significant change at the active sites of SARS-CoV-2. The Ser46 mutation present at the entrance of the S5 subpocket of SARS-CoV-2 increases the contribution of other two hydrophilic residues, while the Phe134 mutation, present in the catalytic cysteine loop, can cause an increase in catalytic efficiency of Mpro by facilitating fast proton transfer from the Cys145 to His41 residue. It was observed that active site remained conserved among Mpro of both SARS-CoVs, except at the entrance of the S5 subpocket, suggesting sustenance of substrate specificity. The second objective was to screen the inhibitory effects of three different data sets (natural products, coronaviruses main protease inhibitors, and FDA-approved drugs) using a structure-based virtual screening approach. A total of 73 hits had a combo score >2.0. Eight different structural scaffold classes were identified, such as one/two tetrahydropyran ring(s), dipeptide/tripeptide/oligopeptide, large (approximately 20 atoms) cyclic peptide, and miscellaneous. The screened hits showed key interactions with subpockets of the active site. Further, molecular dynamics studies of selected screened compounds confirmed their perfect fitting into the subpockets of the active site. This study suggests promising structures that can fit into the SARS-CoV-2 Mpro active site and also offers direction for further lead optimization and rational drug design.

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Synthesis and Identification of Novel Potential Molecules Against COVID-19 Main Protease Through Structure-Guided Virtual Screening Approach.

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