In silico modeling of selected phloroglucinol derivatives from Rhodomyrtus tomentosa: Mechanistic insights into their potential against cervical cancer

Abstract

Cervical cancer remains a major cause of morbidity and mortality worldwide, driven primarily by persistent infection with high-risk HPV types. Natural phloroglucinol derivatives from Rhodomyrtus tomentosa have demonstrated anti-cervical cancer potential; however, their apoptosis-related mechanisms remain insufficiently characterized. In this work, selected phloroglucinol derivatives were evaluated as potential inhibitors of the anti-apoptotic Bcl-2 protein (PDB: 6GL8) through an integrated in silico pipeline that combines molecular docking, 100 ns molecular dynamics simulations, MM/GBSA binding free-energy estimation, ADMET profiling, and DFT-based electronic analysis. Docking prioritized CPD1 as the most favorable ligand (-37.36 kJ/mol), outperforming Belzutifan (-25.73 kJ/mol) and engaging the conserved binding pocket. MD trajectories supported stable complex formation across 100 ns. MM/GBSA further indicated stronger binding for CPD1 (ΔTOTAL = -138.78 ± 15.4 kJ/mol) relative to Belzutifan (-63.72 ± 14.31 kJ/mol), primarily due to more favorable gas-phase interactions, while maintaining a comparable solvation term. ADMET predictions suggested similar solubility but higher intestinal absorption for CPD1, alongside a hERG II alert that warrants cardiotoxicity-oriented optimization. DFT descriptors were consistent with the enhanced electrophilic character of CPD1. Collectively, CPD1 is computationally prioritized as a candidate scaffold for follow-up experimental validation and structure-guided refinement.