Withanone and caffeic acid phenethyl ester are predicted to interact with main protease (M^pro) of SARS-CoV-2 and inhibit its activity

Abstract

The recent novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2/2019-nCoV) has caused a large number of deaths around the globe. There is an urgent need to understand this new virus and develop prophylactic and therapeutic drugs. Since drug development is an expensive, intense and time-consuming path, timely repurposing of the existing drugs is often explored wherein the research avenues including genomics, bioinformatics, molecular modeling approaches offer valuable strengths. Here, we have examined the binding potential of Withaferin-A (Wi-A), Withanone (Wi-N) (active withanolides of Ashwagandha) and Caffeic Acid Phenethyl Ester (CAPE, bioactive ingredient of propolis) to a highly conserved protein, M^pro of SARS-CoV-2. We found that Wi-N and CAPE, but not Wi-A, bind to the substrate-binding pocket of SARS-CoV-2 M^pro with efficacy and binding energies equivalent to an already claimed N3 protease inhibitor. Similar to N3 inhibitor, Wi-N and CAPE were interacting with the highly conserved residues of the proteases of coronaviruses. The binding stability of these molecules was further analyzed using molecular dynamics simulations. The binding free energies calculated using MM/GBSA for N3 inhibitor, CAPE and Wi-N were also comparable. Data presented here predicted that these natural compounds may possess the potential to inhibit the functional activity of SARS-CoV-2 protease (an essential protein for virus survival), and hence (i) may connect to save time and cost required for designing/development, and initial screening for anti-COVID drugs, (ii) may offer some therapeutic value for the management of novel fatal coronavirus disease, (iii) warrants prioritized further validation in the laboratory and clinical tests.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2 coronavirus
• Ashwagandha
• Withanone
• Withaferin-A
• honeybee propolis
• caffeic acid phenethyl ester
• molecular docking
• binding
• main protease (M^pro)

Data availability statement

All data generated or analyzed during this study are included in this published article.

Disclosure statement

No potential conflict of interest is reported by the authors.

Additional information

Funding

This study was supported by the funds granted by AIST (Japan) and Department of Biotechnology (Govt. of India). The computations were performed at the Bioinformatics Centre at IIT Delhi.