New SARS-CoV-2 Mpro Inhibitor by Ascorbic Acid: Design, Molecular Docking, Lipinski’s Rule and ADMET Analysis

Abstract

Background: Mpro protease, an enzyme found in coronaviruses (PDB codes: 6LU7 and 2GTB), provides a unique way to recognize potentially active substances. All of the suggested drugs shared an ethanolamine/propylamine bridge, consisting of two to three lengths of carbon atoms, to treat COVID-19 patients. Because of this, the author chose to conduct the study using ascorbic acid, also known as R-5-(S)-1,2-dihydroxyethyl)-3,4-dihydroxyfuran-2(5H)-one, a potent immune system booster for combating coronavirus. Objective: In this study, ascorbic acid is used to identify new potential inhibitors of the SARS-CoV-2 Mpro enzyme using molecular docking, the Lipinski rule for drug-likeness, physiochemical property by Molinspiration, ADMET by Pre ADMET server, and Osiris property explorer for toxicity analysis in comparison to proposed drug therapy. Methods: The receptor-binding site in the active sites of Mpro protease (PDB codes: 6LU7 and 2GTB) was predicted using molecular docking studies using the GOLD, v5.2.2 program (Genetic Optimization for Ligand Docking). Ascorbic acid derivatives' physiochemical properties, drug-likeness, ADME, and toxicity were further examined using Molinspiration, OSIRIS Property Explorer, and Pre ADMET service. Results: The findings result showed that molecules 16 and 17 had outstanding gold score/energy score with 6LU7 (52.45 & 51.45/-15.16 &-17.32 kJ/mol, respectively) and 2GTB (55.09 & 54.79/-11.86 &-16.31 kJ/mol, respectively). All molecules were found with zero violation of Lipinski rules and showed good bioavailability via the oral route. In comparison to the proposed drugs, the compounds 3, 5, 6, 7, 8, 13, and 17 had good drug scores and received excellent drug-likeness ratings. The compounds 14, 15, 16, and 17 were observed as remarkable inhibitors for CYP 450 3A4, CYP 450 2C9 and CYP 450 2C19 and for CYP 450 3A4 and CYP 450 2D6. Conclusion: In the molecular docking study, compound 17 showed outstanding gold/energy values as well as excellent bioactivity scores against GPCR, protease inhibitors, and kinase inhibitors. Drug-related attributes were obtained using OSIRIS property explorer and pre-ADME, which showed compound 17 to have an excellent drug score, no toxicity, and drug-likeness. © 2024 Bentham Science Publishers.