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

• Published in: Journal of chemical information and modeling Vol. 61; no. 2; pp. 1020 - 1032
• Main Authors: Manandhar, Anjela, Blass, Benjamin E, Colussi, Dennis J, Almi, Imane, Abou-Gharbia, Magid, Klein, Michael L, Elokely, Khaled M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22.02.2021
• Subjects: Antiviral Agents - pharmacology; Binding sites; Computer Simulation; Coronaviruses; COVID-19; Crystal structure; Crystallography, X-Ray; Cysteine Proteases - chemistry; Cysteine Proteases - drug effects; Free energy; Humans; In Vitro Techniques; Ligands; Microbial Sensitivity Tests; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Pandemics; Pharmaceutical Modeling; Protease; Protease inhibitors; Protein Conformation; SARS-CoV-2 - drug effects; SARS-CoV-2 - enzymology; Serine Proteases; Serine Proteinase Inhibitors - pharmacology; Severe acute respiratory syndrome coronavirus 2; Viral diseases; Viral Nonstructural Proteins - antagonists & inhibitors; Water chemistry
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.0c01457

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.