Pharmacoinformatics and molecular dynamics simulation studies reveal potential covalent and FDA-approved inhibitors of SARS-CoV-2 main protease 3CLpro. Issue 13 (2nd September 2021)

• Record Type: Journal Article
• Authors: Alamri, Mubarak A.; Tahir ul Qamar, Muhammad; Mirza, Muhammad Usman; Bhadane, Rajendra; Alqahtani, Safar M.; Muneer, Iqra; Froeyen, Matheus; Salo-Ahen, Outi M. H.
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 39:Issue 13(2021)
• Page Start: 4936
• Page End: 4948
• Publication Date: 2021-09-02
• Subjects: SARS-CoV-2 -- COVID-19 -- 3CL protease -- covalent inhibitors -- paritaprevir -- simeprevir -- molecular dynamics simulation; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2020.1782768
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: The SARS-CoV-2 was confirmed to cause the global pandemic of coronavirus disease 2019 (COVID-19). The 3-chymotrypsin-like protease (3CLpro), an essential enzyme for viral replication, is a valid target to combat SARS-CoV and MERS-CoV. In this work, we present a structure-based study to identify potential covalent inhibitors containing a variety of chemical warheads. The targeted Asinex Focused Covalent (AFCL) library was screened based on different reaction types and potential covalent inhibitors were identified. In addition, we screened FDA-approved protease inhibitors to find candidates to be repurposed against SARS-CoV-2 3CLpro. A number of compounds with significant covalent docking scores were identified. These compounds were able to establish a covalent bond (C–S) with the reactive thiol group of Cys145 and to form favorable interactions with residues lining the substrate-binding site. Moreover, paritaprevir and simeprevir from FDA-approved protease inhibitors were identified as potential inhibitors of SARS-CoV-2 3CLpro. The mechanism and dynamic stability of binding between the identified compounds and SARS-CoV-2 3CLpro were characterized by molecular dynamics (MD) simulations. The identified compounds are potential inhibitors worthy of further development as COVID-19 drugs. Importantly, the identified FDA-approved anti-hepatitis-C virus (HCV) drugs paritaprevir and simeprevir could be ready for clinical trials to treat infected patients and help curb COVID-19. Communicated by Ramaswamy H. Sarma