Prevention of SARS-CoV-2 Proliferation with a Novel and Potent Main Protease Inhibitor by Docking, ADMET, MM-PBSA, and Molecular Dynamics Simulation

Abstract

COVID-19 is the last disease caused by SARS-CoV-2 associated with a severe immune response and lung damage. The main protease (Mpro) has a vital role in SARS-CoV-2 proliferation. Moreover, humans lack homologous Mpro, which makes the Mpro a suitable drug target for the development of SARS-CoV-2 drugs. The purchasable L5000 library (Selleckchem Inc) includes 99,040 compounds that were used for virtual screening. After molecular docking and ADME studies, we selected a compound (WAY-604395) with a potent binding affinity to the Mpro active site and acceptable ADME properties compared to the reference drug (nelfinavir). Molecular dynamics (MD) simulation outcomes have proved that the Mpro-WAY604395 complex possesses a considerable value of flexibility, stability, compactness and binding energy. Our Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculation demonstrates that WAY-604395 is more potent ([Formula: see text]272.19[Formula: see text]kcal mol[Formula: see text]) in comparison with nelfinavir ([Formula: see text]173.39[Formula: see text]kcal[Formula: see text]mol[Formula: see text]) against SARS-CoV-2 Mpro. In conclusion, we suggest that WAY-604395 has the potential for the treatment of SARS-CoV-2 by inhibition of the Mpro.