Identification of natural compounds as potent inhibitors of SARS-CoV-2 main protease using combined docking and molecular dynamics simulations

Deeba Shamim Jairajpuri; Afzal Hussain; Khalida Nasreen; Taj Mohammad; Farah Anjum; Md Tabish Rehman; Gulam Mustafa Hasan; Mohamed F Alajmi; Md Imtaiyaz Hassan

doi:10.1016/j.sjbs.2021.01.040

Identification of natural compounds as potent inhibitors of SARS-CoV-2 main protease using combined docking and molecular dynamics simulations

Saudi J Biol Sci. 2021 Apr;28(4):2423-2431. doi: 10.1016/j.sjbs.2021.01.040. Epub 2021 Jan 27.

Authors

Deeba Shamim Jairajpuri¹, Afzal Hussain², Khalida Nasreen³, Taj Mohammad³, Farah Anjum⁴, Md Tabish Rehman², Gulam Mustafa Hasan⁵, Mohamed F Alajmi², Md Imtaiyaz Hassan³

Affiliations

¹ Department of Medical Biochemistry, College of Medicine and Medical Sciences, Arabian Gulf University, P.O. Box 22971, Manama, Bahrain.
² Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
³ Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
⁴ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia.
⁵ Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, P.O. Box 173 Al-Kharj, 11942, Saudi Arabia.

Abstract

Coronavirus disease 2019 (COVID-19) has emerged from China and globally affected the entire population through the human-to-human transmission of a newly emerged virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The genome of SARS-CoV-2 encodes several proteins that are essential for multiplication and pathogenesis. The main protease (M^pro or 3CL^pro) of SARS-CoV-2 plays a central role in its pathogenesis and thus is considered as an attractive drug target for the drug design and development of small-molecule inhibitors. We have employed an extensive structure-based high-throughput virtual screening to discover potential natural compounds from the ZINC database which could inhibit the M^pro of SARS-CoV-2. Initially, the hits were selected on the basis of their physicochemical and drug-like properties. Subsequently, the PAINS filter, estimation of binding affinities using molecular docking, and interaction analyses were performed to find safe and potential inhibitors of SARS-CoV-2 M^pro. We have identified ZINC02123811 (1-(3-(2,5,9-trimethyl-7-oxo-3-phenyl-7H-furo[3,2-g]chromen-6-yl)propanoyl)piperidine-4-carboxamide), a natural compound bearing appreciable affinity, efficiency, and specificity towards the binding pocket of SARS-CoV-2 M^pro. The identified compound showed a set of drug-like properties and preferentially binds to the active site of SARS-CoV-2 M^pro. All-atom molecular dynamics (MD) simulations were performed to evaluate the conformational dynamics, stability and interaction mechanism of M^pro with ZINC02123811. MD simulation results indicated that M^pro with ZINC02123811 forms a stable complex throughout the trajectory of 100 ns. These findings suggest that ZINC02123811 may be further exploited as a promising scaffold for the development of potential inhibitors of SARS-CoV-2 M^pro to address COVID-19.

Keywords: Drug discovery; Molecular dynamics simulation; Natural compounds; SARS-CoV-2 main protease; Small molecule inhibitors; Virtual high-throughput screening.