In silico identification of novel benzophenone–coumarin derivatives as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors

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

Keywords:

• SARS-CoV-2
• RdRp
• BCDs
• BCD-8
• antiviral property
• in silico approach

Acknowledgment

Authors are thankful to the JSS AHER for their kind support and necessary facilities. This study doesn't include any animal or human study.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author’s contributions

RR contributed to conceptualization, supervision, investigation; SMP and RMM performed molecular docking and dynamics studies; SMP and PS performed drug likeliness and pharmacokinetic analysis; AP, JCS and VLR contributed to methodology and software data analysis; all the authors have contribution in writing – original draft preparation, formal analysis, visualization, reviewing and editing.