Repurposing of FDA-approved drugs as potential inhibitors of the SARS-CoV-2 main protease: Molecular insights into improved therapeutic discovery. (March 2022)

• Record Type: Journal Article
• Authors: Ray, Abhik Kumar; Sen Gupta, Parth Sarthi; Panda, Saroj Kumar; Biswal, Satyaranjan; Bhattacharya, Uddipan; Rana, Malay Kumar
• Is Part Of: Computers in biology and medicine. Volume 142(2022)
• Publication Date: 2022-03
• Subjects: SARS-CoV-2 -- Main protease -- FDA-Approved drugs -- Molecular dynamics -- Binding free energy; Medicine -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; 610.285
• DOI: 10.1016/j.compbiomed.2021.105183
• Languages: English
• ISSNs: 0010-4825

Abstract

Abstract: With numerous infections and fatalities, COVID-19 has wreaked havoc around the globe. The main protease (Mpro), which cleaves the polyprotein to form non-structural proteins, thereby helping in the replication of SARS-CoV-2, appears as an attractive target for antiviral therapeutics. As FDA-approved drugs have shown effectiveness in targeting Mpro in previous SARS-CoV(s), molecular docking and virtual screening of existing antiviral, antimalarial, and protease inhibitor drugs were carried out against SARS-CoV-2 Mpro. Among 53 shortlisted drugs with binding energies lower than that of the crystal-bound inhibitor α-ketoamide 13 b (−6.7 kcal/mol), velpatasvir, glecaprevir, grazoprevir, baloxavir marboxil, danoprevir, nelfinavir, and indinavir (−9.1 to −7.5 kcal/mol) were the most significant on the list (hereafter referred to as the 53-list). Molecular dynamics (MD) simulations confirmed the stability of their Mpro complexes, with the MMPBSA binding free energy (ΔGbind ) ranging between −124 kJ/mol (glecaprevir) and −28.2 kJ/mol (velpatasvir). Despite having the lowest initial binding energy, velpatasvir exhibited the highest ΔGbind value for escaping the catalytic site during the MD simulations, indicating its reduced efficacy, as observed experimentally. Available inhibition assay data adequately substantiated the computational forecast. Glecaprevir and nelfinavir (ΔGbind = −95.4 kJ/mol) appear to be the most effective antiviral drugs against Mpro. Furthermore, the remaining FDA drugs on the 53-list can be worth considering, since some have already demonstrated antiviral activity against SARS-CoV-2. Hence, theoretical pKi (Ki = inhibitor constant) values for all 53 drugs were provided. Notably, ΔGbind directly correlates with the average distance of the drugs from the His41–Cys145 catalytic dyad of Mpro, providing a roadmap for rapid screening and improving the inhibitor design against SARS-CoV-2 Mpro. Graphical abstract: Image 1 Highlights: All protease inhibitor, antiviral, and antimalarial FDA-approved drugs were screened against the SARS-CoV-2 main protease. 53 drugs exhibited interaction energy with Mpro below −7.0 kcal/mol and their pKi values were predicted. Among the top 7 drugs considered for the 100 ns MD simulation, Velpatasvir showed affinity for allosteric sites. Glecaprevir and nelfinavir showed inhibitory potential with the lowest binding free energies with Mpro in post-MD analyses. The predicted relationship between binding free energy and catalytic dyad's distance was supported by experimental findings.