Arylamines QSAR-Based Design and Molecular Dynamics of New Phenylthiophene and Benzimidazole Derivatives with Affinity for the C111, Y268, and H73 Sites of SARS-CoV-2 PLpro Enzyme.

Abstract

A non-structural SARS-CoV-2 protein, PLpro, is involved in post-translational modifications in cells, allowing the evasion of antiviral immune response mechanisms. In this study, potential PLpro inhibitory drugs were designed using QSAR, molecular docking, and molecular dynamics. A combined QSAR equation with physicochemical and Free-Wilson descriptors was formulated. The r2, q2, and r2test values were 0.833, 0.770, and 0.721, respectively. From the equation, it was found that the presence of an aromatic ring and a basic nitrogen atom is crucial for obtaining good antiviral activity. Then, a series of structures for the binding sites of C111, Y268, and H73 of PLpro were created. The best compounds were found to exhibit pIC50 values of 9.124 and docking scoring values of -14 kcal/mol. The stability of the compounds in the cavities was confirmed by molecular dynamics studies. A high number of stable contacts and good interactions over time were exhibited by the aryl-thiophenes Pred14 and Pred15, making them potential antiviral candidates.