Outcomes of various clinical studies for the coronavirus disease 2019 (COVID-19) treatment indicated that the drug acts via inhibition of multiple pathways (targets) is likely to be more successful and promising. Keeping this hypothesis intact, the present study describes for the first-time, Grazoprevir, an FDA approved anti-viral drug primarily approved for Hepatitis C Virus (HCV), mediated multiple pathway control via synergistic inhibition of viral entry targeting host cell Angiotensin-Converting Enzyme 2 (ACE-2)/transmembrane serine protease 2 (TMPRSS2) and viral replication targeting RNA-dependent RNA polymerase (RdRP). Molecular modeling followed by in-depth structural analysis clearly demonstrated that Grazoprevir interacts with the key residues of these targets. Futher, Molecular Dynamics (MD) simulations showed stability and burial of key residues after the complex formation. Finally, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis identified the governing force of drug-receptor interactions and stability. Thus, we believe that Grazoprevir could be an effective therapeutics for the treatment of the COVID-19 pandemic with a promise of unlikely drug resistance owing to multiple inhibitions of eukaryotic and viral proteins, thus warrants further clinical studies.
【저자키워드】 Computational biophysics, Drug discovery and development, TMPRSS2, 【초록키워드】 COVID-19, Treatment, coronavirus disease, COVID-19 pandemic, Dynamics, Viral proteins, FDA, viral entry, HCV, stability, viral replication, hepatitis C, pathway, Clinical studies, RNA-dependent RNA polymerase, targets, drug resistance, surface, anti-viral drug, clinical study, Interaction, Hypothesis, Analysis, Structural analysis, host cell, Grazoprevir, Mechanics, complex, residue, serine protease, effective, synergistic, indicated, approved, unlikely, demonstrated, interact, Area, eukaryotic, Keeping, multiple pathway, 【제목키워드】 Replication, novel corona virus, Grazoprevir,