Title: Virtual screening of plant phytochemicals to discover potent Janus kinase-1 inhibitors against severe COVID-19 and sepsis

Authors: Kavita Joshi; Shradheya R.R. Gupta; Shubham Verma; Rakesh Sharma; Sameer Qureshi; Mansoor Ali Syed; Vandana Nunia

Addresses: Department of Zoology, University of Rajasthan, Jaipur, 302004, Rajasthan, India ' Bioinformatics Infrastructure Facility (DBT-BIF), University of Rajasthan, Jaipur, 302004, Rajasthan, India ' Bioinformatics Infrastructure Facility (DBT-BIF), Centre for Converging Technologies, University of Rajasthan, Jaipur, 302004, Rajasthan, India ' Bioinformatics Infrastructure Facility (DBT-BIF), University of Rajasthan, Jaipur, 302004, Rajasthan, India ' Department of Zoology, University of Rajasthan, Jaipur, 302004, Rajasthan, India ' Department of Biotechnology, Jamia MilliaIslamia, New Delhi, 110025, India ' Department of Zoology, University of Rajasthan, Jaipur, 302004, Rajasthan, India

Abstract: Janus kinases (JAK) are intracellular tyrosine kinases that transduce cytokine-mediated signals and play a major role in the progression of multiple organ dysfunction syndrome (MODS) caused by sepsis and virus-induced SARSCOVID-19. In this study, we focused on finding the potential phytochemicals to inhibit JAK1. We prepared and screened a library of 5229 diverse phytochemicals and filtered out 2081 compound based on drug likeness properties. These compounds were docked with the JAK1 kinase domain with Upadacitinib, (a FDA approved JAK-1 inhibitor) used as reference. We have further shortlist the compounds based on their docking binding energy, which was higher than that Upadacitinib. The top four compounds Kudzuisoflavone B, Taiwaniaflavone 7-O-methyl ether, Formosanatin D, and Withaphysalin A, showed binding energy -12 Kcal/mol, were further subjected to dynamic simulation. Based on the RMSD, RMSF, H-bond, hydrophobic interactions, MMPBSA and GROMACS total energy, Kudzuisoflavone B was selected as potent Jak-1 inhibitor among all compounds.

Keywords: JAK; Janus kinase; SARS-CoV-2 virus; sepsis; virtual drug screening; phytochemical inhibitors; Upadacitinib; molecular docking; molecular dynamic simulation; MMPBSA; Kudzuisoflavone B.

DOI: 10.1504/IJCBDD.2023.133834

International Journal of Computational Biology and Drug Design, 2023 Vol.15 No.5, pp.391 - 411

Received: 28 Dec 2021
Received in revised form: 25 Jul 2022
Accepted: 18 Sep 2022
Published online: 04 Oct 2023 *

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