Medicinal fungi-derived secondary metabolites as potential inhibitors of DNA polymerase beta: a computational approach against liver cancer

Abstract

Background: Hepatocellular carcinoma (HCC) remains a major global health burden with high mortality rates and limited therapeutic options. DNA polymerase beta (Pol β), a key enzyme in base excision repair, is implicated in tumor progression and chemoresistance, making it an emerging target in cancer therapy. Natural products, particularly secondary metabolites from medicinal fungi, offer promising scaffolds for anticancer drug development. Objective: This study aimed to identify and evaluate medicinal fungi-derived secondary metabolites with inhibitory potential against Pol β using an integrative computational approach. Methods: A virtual screening workflow was applied to 1,830 secondary metabolites from the MEFSAT database. Ligand preparation was followed by molecular docking (HTVS, SP, XP), MM-GBSA binding free energy calculations, and electronic structure analysis using density functional theory (DFT). Further evaluation included QTAIM analysis, electrostatic potential mapping, and in silico toxicity and ADMET profiling. Results: The top five compounds—Phellibaumin A, Eriodictyol, Flazin, Daldinone B, and Catechin—showed strong binding affinities within the DNA-binding pocket of Pol β, supported by favorable docking scores and MM-GBSA energies. DFT-derived descriptors (e.g., energy gap, electrophilicity index), QTAIM parameters, and ESP surfaces indicated high reactivity and binding propensity, particularly for Phellibaumin A. Toxicity (ProTox 3.0) and pharmacokinetic (SwissADME) evaluations highlighted Phellibaumin A as the most promising candidate, with low hepatotoxicity, high oral bioavailability, and good synthetic accessibility. Conclusion: This study demonstrates the potential of fungal secondary metabolites as DNA Pol β inhibitors for liver cancer therapy. Phellibaumin A emerged as a lead compound based on its electronic, pharmacological, and toxicological profiles. These findings support further experimental validation and optimization of mushroom-derived molecules for HCC treatment.