key: cord-0702839-angwbp0q
authors: Prajapati, Jignesh; Patel, Rohit; Goswami, Dweipayan; Saraf, Meenu; Rawal, Rakesh M.
title: Sterenin M as a potential inhibitor of SARS-CoV-2 main protease identified from MeFSAT database using molecular docking, molecular dynamics simulation and binding free energy calculation()()()
date: 2021-06-12
journal: Comput Biol Med
DOI: 10.1016/j.compbiomed.2021.104568
sha: 185b5fdcf04d7f3c4d14ede70fc22ce7037d90dd
doc_id: 702839
cord_uid: angwbp0q

The disease outbreak of Coronavirus disease-19 (COVID-19), caused by the novel SARS-CoV-2 virus, remains a public health concern. COVID-19 is spreading rapidly with a high mortality rate due to unavailability of effective treatment or vaccine for the disease. The high rate of mutation and recombination in SARS-CoV2 makes it difficult for scientist to develop specific anti-CoV2 drugs and vaccines. SARS-CoV-2-Mpro cleaves the viral polyprotein to produce a variety of non-structural proteins, but in human host it also cleaves the nuclear transcription factor kappa B (NF-κB) essential modulator (NEMO), which suppresses the activation of the NF-κB pathway and weakens the immune response. Since the main protease (Mpro) is required for viral gene expression and replication, it is a promising target for antagonists to treat novel coronavirus disease and discovery of high resolution crystal structure of SARS-CoV-2-Mpro provide an opportunity for in silico identification of its possible inhibitors. In this study we intend to find novel and potential Mpro inhibitors from around 1830 chemically diverse and therapeutically important secondary metabolites available in the MeFSAT database by performing molecular docking against the Mpro structure of SARS-CoV-2 (PDB ID: 6LZE). After ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and binding energy calculation through MM-GBSA for top five hits, Sterenin M was proposed as a SARS-CoV2-Mpro inhibitor with validation of molecular dynamics (MD) simulation study. Sterenin M seems to have the potential to be a promising ligand against SARS-CoV-2, and thus it requires further validation by in vitro and in vivo studies.

The whole world is suffering from current unique and dynamic coronavirus 77 disease 2019 (COVID-19) pandemic, due to the global outbreak of the severe acute 78 respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 emerged in late 79 December 2019 in Wuhan, China's Hubei province, and then spread across the globe, 80 affecting millions of people [1] . In massive populations, it primarily causes respiratory 81 or gastrointestinal sickness with symptoms like fever, pneumonia, diarrhoea vomiting 82 and shortness of breath that needs urgent intensive care [2] . As of 7 th April 2021, more for suppressing the host's immune system [7] . They act as IFN antagonist by cleaving 113 the nuclear transcription factor kappa B (NF-κB) essential modulator (NEMO), which is 114 essential for activation of NF-κB pathway [8] . It has been reported that, the Mpro of 115 PDCoV also impairs the JAK-STAT pathway [9] . As a result, developing quintessential 116 enzyme Mpro specific inhibitors would be crucial for blocking viral replication and 117 preventing host immune system suppression without any toxicity due to unavailability 118 of Mpro human analogue. 119 In order to develop potential SARS-CoV-2 Mpro blocker, two compounds 11a and 120 11b have been designed based on the knowledge of active residue of the binding site 121 and developed synthetically which showed 100% and 96% inhibition activity at 1 µM, The X-ray crystal structure of SARS-CoV-2 main protease (Mpro) in complex with CoV2-Mpro and showed binding energy close to known Mpro inhibitors were selected.

The Glide Score and interacting amino acid residues of the selected lead molecules and 272 five Mpro antagonists presented in Table 1 . Table 2 . Enokipodin D, all of the compounds were discovered to be substrates, implying that 303 they can move through the cell membrane through the ABC transporter. Besides this, 304 Poh 3 and Sterenin M were found to be ineffective as inhibitors for P-glycoprotein I and 305 II transporters, implying that they are unable to inhibit both of these drug efflux pumps. Table 3 along with other essential ADMET properties. Table 4 . Table 1 Docking scores and the contributing binding residues of known Mpro inhibitors and 698 selected top five fungal metabolites generated using XP docking. 699

Glide Score (Kcal/mol) Contributing Binding Residues

-8.255 

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