Bioactivity of benzophenazine enaminone derivatives as inhibitors of ERK2 based on molecular docking and dynamics simulation studies

Abstract

Molecular docking is a commonly employed technique in structure-based drug design that generates the binding pose and affinity between ligands and targets. In the present study nine benzo[a]phenazin enaminone derivatives containing substituted aryl and heteroaryl amines were subjected to molecular docking (Auto Dock 4.2) studies for the inhibition of the ERK2 (Extracellular Signal-Regulated Kinase 2). The in silico molecular docking study results showed that, compounds D and E having minimum binding energy and have good affinity toward the active pocket. The compounds demonstrated comparable binding free energies, each at -10.5 kcal/mol, with the ligand binding sites located at ASP109(A) and the 1-H bonds positioned within a distance range of 2.98-2.99 Å. However, these compounds showed a higher ERK2 inhibitory effect compared to Purvalanol, the standard drug, which had a binding free energy of -7.5 kcal/mol. Purvalanol bound to the ligand binding sites at Met106(A) and Asn152(A), with the 2-H bonds situated at distances of 2.99 Å and 3.17 Å, respectively. Furthermore, the RMSD value for compounds D and E stabilizes around a consistent fixed value of 1.5, indicating a stable protein conformation. Moreover, molecular dynamics (MD) studies were conducted to evaluate the stability of the docked complexes with ligands D and E. We hypothesize that these compounds may inhibit ERK2 and could potentially be used as drugs for cancer treatment. Therefore, they can be regarded as potent inhibitors of ERK2 and effective anticancer compounds for therapeutic application.