Anti-SARS-CoV-2 drugs are urgently needed to prevent the pandemic and for immunization. Their protease inhibitor treatment for COVID-19 has been used in clinical trials. In Calu-3 and THP1 cells, 3CL SARS-CoV-2 Mpro protease is required for viral expression, replication, and the activation of the cytokines IL-1, IL-6, and TNF-. The Mpro structure was chosen for this investigation because of its activity as a chymotrypsin-like enzyme and the presence of a cysteine-containing catalytic domain. Thienopyridine derivatives increase the release of nitric oxide from coronary endothelial cells, which is an important cell signaling molecule with antibacterial activity against bacteria, protozoa, and some viruses. Using DFT calculations, global descriptors are computed from HOMO-LUMO orbitals; the molecular reactivity sites are analyzed from an electrostatic potential map. NLO properties are calculated, and topological analysis is also part of the QTAIM studies. Both compounds 1 and 2 were designed from the precursor molecule pyrimidine and exhibited binding energies (-14.6708 kcal/mol and -16.4521 kcal/mol). The binding mechanisms of molecule 1 towards SARS-COV-2 3CL Mpro exhibited strong hydrogen bonding as well as Vdw interaction. In contrast, derivative 2 was bound to the active site protein's active studied that several residues and positions, including (His41, Cys44, Asp48, Met49, Pro52, Tyr54, Phe140, Leu141, Ser144, His163, Ser144, Cys145, His164, Met165, Glu166, Leu167, Asp187, Gln189, Thr190, and GLn192) are critical for the maintenance of inhibitors inside the active pocket. Molecular docking and 100 ns MD simulation analysis revealed that Both compounds 1 and 2 with higher binding affinity and stability toward the SARS-COV-2 3CL Mpro protein. Binding free energy calculations and other MD parameters support the finding.Communicated by Ramaswamy H. Sarma.
Keywords: ADMET; AIM analysis; NLO; QTAIM; Styrylthieno[2,3-b]pyridine-2-carboxamide; molecular docking; molecular dynamics.