Molecular Docking, Molecular Dynamics Simulation, and MM/GBSA Studies of (N-(4-Carbamoylphenyl)-8-cyclopropyl-7-(naphthalen-1-ylmethyl)-5-oxo-2,3-dihydro-[1,3]thiazolo[3,2-a]pyridine-3-carboxamide for Its Potential Use Against SARS-CoV-2

Coronavirus disease 2019 (COVID-19) is a pandemic disease caused by the SARS-coronavirus-2, which has a high rate of infection. Regardless of the advancements made in the creation of vaccines, it is urgently necessary to identify antiviral substances that can more effectively combat the SARS-coronavirus-2. The SARS-coronavirus-2 main protease is essential for viral transcription and replication. Using molecular docking, molecular dynamics simulation, and free binding energy calculations based on molecular mechanics/generalized Born surface area (MM/GBSA) approaches, an in silico technique was used in this study to help clarify the inhibitory potential of (N-(4-carbamoylphenyl)-8-cyclopropyl-7-(naphthalen-1-ylmethyl)-5-oxo-2,3-dihydro-[1,3]thiazolo[3,2-a]pyridine-3-carboxamide (aka, compound 36) against the main protease of SARS-coronavirus-2. Four software programs: AutoDockFR, AutoDock Vina v1.2.3, CABS-Flex2.0, and fastDRH servers were used to investigate the proteins binding sites, docked the ligands into the crystal structure of SARS-coronavrus-2 Mpro, check the stability of the complexes using molecular dynamics simulations, and MM/GBSA calculations, respectively. The standard drugs have all shown positive interactions with the main protease of the virus, but compound 36 has the highest negative binding affinity of them all. Computer-aided drug design was used to create a few compound 36 derivatives, and pharmacokinetic studies and molecular docking studies were conducted to assess their drug-like characteristics. These compounds (D3 and D6) have better binding affinities than the template and the conventional drugs. The top-scoring conformational complexes were subjected to molecular dynamics (MD) simulations in the following section of the study to further examine the complexes stability and the interactions between the ligand and receptor. The MM/GBSA further demonstrated that net free binding energies were primarily raised by Van der Waals interactions. The present investigation serves as a foundation for investigating the improved binding capacities and structural characteristics of SARS-CoV-2 Mpro variants to develop fresh anti-viral drugs.