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

• Published in: Chemistry & biodiversity 2024-11, Vol.21 (11), p.e202401238-n/a
• Main Authors: Ibrahim, Mahmoud A. A., Ali, Sara S. M., Abdelrahman, Alaa H. M., Abdeljawaad, Khlood A. A., Sidhom, Peter A., Sayed, Shaban R. M., El‐Tayeb, Mohamed A., Paré, Paul W., Hegazy, Mohamed‐Elamir F.
• Format: Article
• Language: English
• Subjects: Acids; Affinity; anticancer drug; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Clinical trials; Crystallization; Data Mining; database mining; Extracellular signal-regulated kinase; Extracellular signal-regulated kinase 2 (ERK2); Humans; Inhibitors; Kinases; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Molecular Structure; NPACT database; Phytochemicals - chemistry; Phytochemicals - metabolism; Phytochemicals - pharmacology; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proteins; Simulation; Thermodynamics; Toxicity
• ISSN: 1612-1872; 1612-1880; 1612-1880
• DOI: 10.1002/cbdv.202401238

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 (ΔGbinding) 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 ΔGbinding 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.