In silico identification of novel benzophenone–coumarin derivatives as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors. Issue 23 (19th December 2022)

• Record Type: Journal Article
• Authors: Patil, Shashank M.; Martiz, Reshma Mary; Ramu, Ramith; Shirahatti, Prithvi S.; Prakash, Ashwini; Chandra S, Jagadeep; Ranganatha, V. Lakshmi
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 40:Issue 23(2022)
• Page Start: 13032
• Page End: 13048
• Publication Date: 2022-12-19
• Subjects: SARS-CoV-2 -- RdRp -- BCDs -- BCD-8 -- antiviral property -- in silico approach; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2021.1978322
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: In this study, we propose our novel benzophenone–coumarin derivatives (BCDs) as potent inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 virus, one of the key targets that are involved in the viral genome replication. We aim to evaluate the in silico antiviral potential of BCDs against this protein target, which involves molecular docking simulations, druglikeliness and pharmacokinetic evaluations, PASS analysis, molecular dynamics simulations, and computing binding free energy. Out of all the BCDs screened through these parameters, BCD-8 was found to be the most efficient and potent inhibitor of SARS-CoV-2 RdRp. During molecular docking simulation, BCD-8 showed an extensive molecular interaction in comparison with that of the standard control used, remdesivir. The druglikeliness and pharmacokinetic analyses also proved the efficiency of BCD-8 as an effective drug without adverse effects. Further, pharmacological potential analysis through PASS depicted the antiviral property of BCD-8. With these findings, we performed molecular dynamics simulations, where BCD-8 edged out remdesivir with its exemplary stable interaction with SARS-CoV-2 RdRp. Furthermore, binding free energy of both BCD-8 and remdesivir was calculated, where BCD-8 showed a lower binding energy and standard deviations in comparison with that of remdesivir. Moreover, being a non-nucleoside analogue, BCD-8 can be used effectively against SARS-CoV-2, whereas nucleoside analogues like remdesivir may become non-functional or less functional due to exonuclease activity of nsp14 of the virus. Therefore, we propose BCD-8 as a SARS-CoV-2 RdRp inhibitor, showing higher predicted efficiency than remdesivir in all the in silico experiments conducted. Communicated by Ramaswamy H. Sarma