Evaluation of novel Anti-SARS-CoV-2 compounds by targeting nucleoprotein and envelope protein through homology modeling, docking simulations, ADMET, and molecular dynamic simulations with the MM/GBSA calculation

Abstract

The current prominent virus that induces severe acute respiratory syndrome is SARS-CoV-2. The incidence of COVID-19 cases is increasing, necessitating the immediate development of effective treatments. Our objective was to employ an in-silico approach to evaluate the effectiveness of conventional compounds against COVID-19’s nucleoprotein and envelope protein. A docking simulation was performed on 9 compounds as SARS-coronavirus inhibitors using AMDock software. Anti-covid-19 activities were further evaluated for the compounds. Based on docking results, the binding affinity of “N-(4-carbamoylphenyl)-8-cyclopropyl-7-(naphthalen-1-ylmethyl)-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxamide,” also called compound 36 in this research, was found to be -8.8 kcal/mol for the modeled envelope protein and -7.3 kcal/mol for the template envelope protein, while -10.1 kcal/mol for the modeled nucleocapsid proteins (NP) and -8.7 kcal/mol for the template nucleocapsid proteins (NP) of SARS-coronavirus, respectively. The ligand and control drug (ritonavir) with high docking scores were subjected to pharmacological screening, molecular dynamic simulations, and Molecular Mechanics-generalized Born Surface Area (MM/GBSA) calculations. Furthermore, the jobs of pharmacokinetics were assessed, and the outcomes acquired show that the proposed compound 36 includes great oral bioavailability and a capacity to diffuse through various organic boundaries. The protein-ligand complexes were subjected to dynamic simulation analyses with a re-enactment time of 10 ns, likewise, their free binding energy was inspected operating the MM/GBSA approach. The docking (MD simulation) results acquired emphasize the pivotal residues answerable for the proteinligand interaction, giving an understanding of the method of association. The MD simulation analysis verifies the structural stability of the selected complexes during the MD trajectory, with minor changes detected. The MM/GBSA data show that compound 36 has the lowest free energy of -12.498 kcal/mol for EP and -57.5185 kcal/mol for NP proteins of SARS-coronavirus, confirming the molecular docking result. As a result, the identified chemical can be used to develop a new family of antiviral medications against SARS-coronavirus-2.

Keywords

SARS-Coronavirus / Comparative modeling / Docking / Molecular dynamics simulation / And MM/GBSA calculation

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