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    Targeting SARS-CoV-2 M3CLpro by HCV NS3/4a Inhibitors: In Silico Modeling and In Vitro Screening

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    Name:
    Elokely-PrePrint-2021-02.pdf
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    Genre
    Pre-print
    Date
    2021-02-04
    Author
    Manandhar, Anjela
    Blass, Benjamin cc
    Colussi, Dennis J.
    Almi, Imane
    Abou-Gharbia, Magid cc
    Klein, Michael L.
    Elokely, Khaled cc
    Group
    Institute of Computational Molecular Science (Temple University)
    Department
    Chemistry
    Pharmaceutical Sciences
    Subject
    Peptides and proteins
    Monomers
    Inhibitors
    Noncovalent interactions
    Screening assays
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/6257
    
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    DOI
    https://doi.org/10.1021/acs.jcim.0c01457
    Abstract
    Currently the entire human population is in the midst of a global pandemic caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus 2). This highly pathogenic virus has to date caused >71 million infections and >1.6 million deaths in >180 countries. Several vaccines and drugs are being studied as possible treatments or prophylactics of this viral infection. M3CLpro (coronavirus main cysteine protease) is a promising drug target as it has a significant role in viral replication. Here we use the X-ray crystal structure of M3CLpro in complex with boceprevir to study the dynamic changes of the protease upon ligand binding. The binding free energy was calculated for water molecules at different locations of the binding site, and molecular dynamics (MD) simulations were carried out for the M3CLpro/boceprevir complex, to thoroughly understand the chemical environment of the binding site. Several HCV NS3/4a protease inhibitors were tested in vitro against M3CLpro. Specifically, asunaprevir, narlaprevir, paritaprevir, simeprevir, and telaprevir all showed inhibitory effects on M3CLpro. Molecular docking and MD simulations were then performed to investigate the effects of these ligands on M3CLpro and to provide insights into the chemical environment of the ligand binding site. Our findings and observations are offered to help guide the design of possible potent protease inhibitors and aid in coping with the COVID-19 pandemic.
    Citation
    Anjela Manandhar, Benjamin E. Blass, Dennis J. Colussi, Imane Almi, Magid Abou-Gharbia, Michael L. Klein, and Khaled M. Elokely Journal of Chemical Information and Modeling 2021 61 (2), 1020-1032 DOI: 10.1021/acs.jcim.0c01457
    Citation to related work
    This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in 'Journal of Chemical Information and Modeling', copyright © American Chemical Society after peer review.
    Has part
    Journal of Chemical Information and Modeling, Vol. 61
    ADA compliance
    For Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
    ae974a485f413a2113503eed53cd6c53
    http://dx.doi.org/10.34944/dspace/6239
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    COVID-19 Research

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