Naturally Occurring Plant‐Based Anticancerous Candidates as Potential ERK2 Inhibitors: In‐Silico Database Mining and Molecular Dynamics Simulations

The evolutionarily conserved extracellular signal‐regulated kinase 2 (ERK2) is involved in regulating cellular signaling in both normal and pathological conditions. ERK2 expression is critical for human development, while hyperactivation is a major factor in tumor progression. Up to now, there have been no approved inhibitors that target ERK2, and as such, here we report on screening of a naturally occurring plant‐based anticancerous compound‐activity‐target (NPACT) database for prospective ERK2 inhibitors. More than 1,500 phytochemicals were screened using in‐silico molecular docking and molecular dynamics (MD) approaches. NPACT compounds with a docking score lower than a co‐crystallized LHZ inhibitor (calc. −10.5 kcal/mol) were subjected to MD simulations. Binding energies (Δ G binding ) of inhibitor‐ERK2 complexes over the MD course were estimated using an MM‐GBSA approach. Based on MM‐GBSA//100 ns MD simulations, the steroid zhankuic acid C (NPACT01034) demonstrated greater binding affinity against ERK2 protein than LHZ, with Δ G binding values of −50.0 and −47.7 kcal/mol, respectively. Structural and energetical analyses throughout the MD course demonstrated stabilization of zhankuic acid C complexed with ERK2 protein. The anticipated ADMET properties of zhankuic acid C indicated minimal toxicity. Moreover, in‐silico evaluation of fourteen ERK2 inhibitors in clinical trials demonstrated the higher binding affinity of zhankuic acid C towards ERK2 protein.