The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is significantly impacting human lives, overburdening the healthcare system and weakening global economies. Plant-derived natural compounds are being largely tested for their efficacy against COVID-19 targets to combat SARS-CoV-2 infection. The SARS-CoV-2 Main protease (Mpro) is considered an appealing target because of its role in replication in host cells. We curated a set of 7809 natural compounds by combining the collections of five databases viz Dr Duke's Phytochemical and Ethnobotanical database, IMPPAT, PhytoHub, AromaDb and Zinc. We applied a rigorous computational approach to identify lead molecules from our curated compound set using docking, dynamic simulations, the free energy of binding and DFT calculations. Theaflavin and ginkgetin have emerged as better molecules with a similar inhibition profile in both SARS-CoV-2 and Omicron variants.

Computer Aided Drug Design Group Chemical Biology Laboratory Center for Cancer Research National Cancer Institute National Institute of Health Frederick MD 21702 USA; Department of Botany Bioinformatics and Climate Change Impacts Management School of Sciences Gujarat University Ahmedabad 380009 Gujarat India

Department of Botany Bioinformatics and Climate Change Impacts Management School of Sciences Gujarat University Ahmedabad 380009 Gujarat India

Department of General Visceral and Thoracic Surgery University Medical Center Hamburg Eppendorf Martinistrasse 52 Hamburg 20246 Germany

Department of Molecular Electrochemistry and Catalysis J Heyrovsky Institute of Physical Chemistry Academy of Sciences of the Czech Republic Dolejskova 2155 3 182 23 Prague 8 Czech Republic; Department of Humanities and Science School of Engineering Indrashil University Mehsana 382740 Gujarat India

Institute of Science Nirma University Ahmedabad 382481 Gujarat India

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