Investigation of ritonavir analogs antiretroviral natural compounds against SARS-CoV-2 envelope protein

Abstract

Since the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported from Wuhan, China, there has been a surge in scientific research to find a permanent cure for the disease. The main challenge in effective drug discovery is the continuously mutating nature of the SARS-CoV-2 virus. Thus, we have used the I-TASSER modeling to predict the structure of the SARS-CoV-2 viral envelope protein followed by combinatorial computational assessment to predict its putative potential small molecule inhibitors. As early treatment with ritonavir in combination was associated with faster time to clinical improvement and/or virological clearance, we aimed to retrieve analogs of ritonavir to find ideal inhibitors for SARS-CoV-2 viral envelope protein. The collected ligands were screened against the predicted binding pocket of viral envelope protein using extra precision (XP) docking protocol and the first four best-docked compounds were studied for complex stability using 300 ns all-atom molecular dynamics simulations embedding within the cellular membrane. Among the selected compounds, ZINC64859171 and ZINC1221429 showed considerable stability and interactions by comparison to the reference compound, i.e., Ritonavir (ZINC3944422). Moreover, the post-simulation analysis suggested the considerable binding affinity and induced conformation changes in the respective docked complexes against Ritonavir. Altogether, the obtained results demonstrated the putative potential of screened ritonavir analogs, i.e., ZINC64859171, against the envelope protein of SARS-CoV-2 and can be considered for further drug development in the treatment of the COVID-19 pandemic.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV2
• envelope protein
• docking
• MD simulation
• PCA analysis
• MMGBSA

Acknowledgments

The authors are highly thankful to Prof. Amaresh Kumar Sahoo, Indian Institute of Information Technology, Prayagraj, India for providing his kind support in binding free energy calculation using the Prime MMGBSA module of Schrodinger Suite 2020-4. The authors are grateful for the support received from Dr. Shiv Bhardwaj, Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences v.v.i., BIOCEV Research Center, Vestec, Czech Republic.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.