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Repurposing drug molecule against SARS-Cov-2 (COVID-19) through molecular docking and dynamics: a quick approach to pick FDA-approved drugs.

ABSTRACT: A novel coronavirus known as severe acute respiratory syndrome is rapidly spreading worldwide. The international health authorities are putting all their efforts on quick diagnosis and placing the patients in quarantine. Although different vaccines have come for quick use as prophylactics, drug repurposing seems to be of paramount importance because of inefficient therapeutic options and clinical trial limitations. Here, we used structure-based drug designing approach to find and check the efficacy of the possible drug that can inhibit coronavirus main protease which is involved in polypeptide processing to functional protein. We performed virtual screening, molecular docking and molecular dynamics simulations of the FDA-approved drugs against the main protease of SARS-CoV-2. Using well-defined computational methods, we identified amprenavir, cefoperazone, riboflavin, diosmin, nadide and troxerutin approved for human therapeutic uses, as COVID-19 main protease inhibitors. These drugs bind to the SARS-CoV-2 main protease conserved residues of substrate-binding pocket and formed a remarkable number of non-covalent interactions. We have found diosmin as an inhibitor which binds covalently to the COVID-19 main protease. This study provides enough evidences for therapeutic use of these drugs in controlling COVID-19 after experimental validation and clinical demonstration.

SUBMITTER: Farhat N

PROVIDER: S-EPMC8487339 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The current crisis of the COVID-19 pandemic around the world has been devastating as many lives have been lost to the novel SARS CoV-2 virus. Thus, there is an urgent need for the right therapeutic drug to curb the disease. However, there is time constraint in drug development, hence the need for drug repurposing approach, a relatively fast and less expensive alternative. In this study, 1,100 Food and Drug Administration (FDA) approved drugs were obtained from DrugBank and trimmed to 791 ligands based on illicitness, withdrawal from the market, being chemical agents rather than drugs, being investigational drugs and having molecular weight greater than 500 (Kg/mol). The ligands were docked against six drug targets of the novel SARS CoV-2 - 3-chymotrypsin-like protease (3CLpro), Angiotensin-converting enzyme (ACE2), ADP ribose phosphatase of NSP3 (NSP3), NSP9 RNA binding protein (NSP9), RNA dependent RNA polymerase (RdRp) and Replicase Polyprotein 1a (RP1a). UCSF Chimera, PyRx and Discovery Studio, were used to prepare the proteins, dock the ligands and visualize the complexes, respectively. Remdesivir, Lopinavir and Hydroxychloroquine were used as reference drugs. Pharmacokinetic properties of the ligands were obtained using AdmetSAR. The binding energies of the standard drugs ranged from -5.4 to -8.7 kcal/mol while over 400 of the ligands screened showed binding energy lower than -5.4 kcal/mol. Out of the 791 number of compounds docked, 10, 91, 132, 92, 54 and 96 compounds showed lower binding energies than all the controls against 3CLPro, ACE2, NSP3, NSP9, RP1a and RdRp, respectively. Ligands that bound all target proteins, and showed the lowest binding energies with good ADMET properties and particularly showed the lowest binding against ACE2 are ethynodiol diacetate (-15.6 kcal/mol), methylnaltrexone (-15.5 kcal/mol), ketazolam (-14.5 kcal/mol) and naloxone (-13.6 kcal/mol). Further investigations are recommended for ethynodiol diacetate, methylnaltrexone, ketazolam and naloxone through preclinical and clinical studies to ascertain their effectiveness.

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Repurposing drug molecule against SARS-Cov-2 (COVID-19) through molecular docking and dynamics: a quick approach to pick FDA-approved drugs.

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