Computational Modeling Reveals Mechanisms of Iridoids from Pterocephalus hookeri as Potential Inhibitors of Hepatocellular Carcinoma
Iranian Journal of Pharmaceutical Sciences,
Vol. 22 No. 1 (2026),
26 Bahman 2026
,
Page 451-465
https://doi.org/10.22037/ijps.v22i1.51121
Abstract
Primary liver cancer remains a significant global health burden, ranking among the most frequently diagnosed malignancies and a leading cause of cancer-related death. Iridoids isolated from Pterocephalus hookeri have demonstrated anti-hepatocellular carcinoma activity; however, their molecular mechanisms, particularly those involving apoptosis regulators, remain unclear. Here, we evaluated iridoid-derived candidates from P. hookeri as potential inhibitors of the anti-apoptotic Bcl-2 protein (PDB: 6GL8) using an integrated in silico workflow comprising molecular docking, 100 ns molecular dynamics simulations, MMGBSA free-energy estimation, ADMET prediction, and DFT calculations. Docking identified CPD6 as the top-ranked ligand (-7.68 kcal/mol), outperforming Paclitaxel (-6.18 kcal/mol) and forming key hydrogen bonds with Gln118 and Arg129. MD simulations supported the stable binding of CPD6-6GL8, with persistent hydrogen-bond occupancy. MMGBSA yielded ΔTOTAL of -27.28 ± 4.80 kcal/mol for CPD6 versus -30.47 ± 7.30 kcal/mol for Paclitaxel, with CPD6 showing favorable gas-phase stabilization but a higher solvation penalty. ADMET suggested comparable solubility and no hepatotoxicity alert for CPD6, though with reduced predicted intestinal absorption. DFT descriptors further characterized CPD6's electronic properties. Overall, CPD6 is a promising Bcl-2 inhibitory scaffold for hepatocellular carcinoma and warrants optimization and experimental validation.
- Anti-apoptosis
- Bcl-2
- DFT
- Iridoids
- Molecular docking
- Pterocephalus hookeri
How to Cite
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