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Structure-Based Virtual Screening to Discover Potential Lead Molecules for the SARS-CoV-2 Main Protease

Journal of Chemical Information and Modeling, 2020-12, Vol.60 (12), p.5781 [Peer Reviewed Journal]

2020. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the associated terms available at https://www.acs.org/content/acs/en/terms.html ;EISSN: 1549-960X ;DOI: 10.1021/acs.jcim.0c00546 ;PMID: 32687345

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Title:
Structure-Based Virtual Screening to Discover Potential Lead Molecules for the SARS-CoV-2 Main Protease
Author: Gahlawat, Anuj ; Kumar, Navneet ; Kumar, Rajender ; Sandhu, Hardeep ; Singh, Inder Pal ; Singh, Saranjit ; Sjöstedt, Anders ; Garg, Prabha
Subjects: Amino Acid Sequence ; Antiviral Agents - chemistry ; Antiviral Agents - metabolism ; Antiviral Agents - pharmacology ; Catalytic Domain ; Coronavirus 3C Proteases - chemistry ; Coronavirus 3C Proteases - metabolism ; COVID-19 - drug therapy ; Databases, Factual ; Drug Design ; Humans ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Mutant Proteins - chemistry ; Mutant Proteins - metabolism ; Protein Conformation ; SARS-CoV-2 - drug effects ; Structure-Activity Relationship ; Viral Protease Inhibitors - chemistry ; Viral Protease Inhibitors - metabolism ; Viral Protease Inhibitors - pharmacology
Is Part Of: Journal of Chemical Information and Modeling, 2020-12, Vol.60 (12), p.5781
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 (M ) in viral replication and gene expression makes this enzyme an attractive drug target. Therefore, inhibition of SARS-CoV-2 M 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 M by facilitating fast proton transfer from the Cys145 to His41 residue. It was observed that active site remained conserved among M 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 M active site and also offers direction for further lead optimization and rational drug design.
Publisher: United States: American Chemical Society
Language: English
Identifier: EISSN: 1549-960X
DOI: 10.1021/acs.jcim.0c00546
PMID: 32687345
Source: Coronavirus Research Database

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Structure-Based Virtual Screening to Discover Potential Lead Molecules for the SARS-CoV-2 Main Protease

2020. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the associated terms available at https://www.acs.org/content/acs/en/terms.html ;EISSN: 1549-960X ;DOI: 10.1021/acs.jcim.0c00546 ;PMID: 32687345

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