Integrated In Silico Discovery of Bioactive Compounds from Kaempferia galanga L. Targeting Estrogen Receptor-β

Abstract

Introduction: Estrogen receptor-β (ERβ) has emerged as a promising molecular target for the development of safer therapeutic agents for estrogen receptor-positive breast cancer due to its anti-proliferative and tumor-suppressive functions Aims: This study aimed to identify potential ERβ-targeting compounds from K. galanga through an integrated in silico approach combining molecular docking, protein–ligand interaction analysis, pharmacokinetic prediction, and toxicity evaluation. Methods: Eighteen phytochemical constituents of K. galanga were screened against the human ERβ ligand-binding domain (PDB ID: 1QKM) using AutoDock Vina. Docking protocol validation was performed by redocking the native ligand, while pharmacokinetic and toxicity profiles were predicted using ADMETlab 2.0. Results: Docking validation produced an RMSD value of 0.3460 Å, confirming the reliability of the docking protocol. Among the investigated compounds, 3-carene-5-one exhibited the strongest binding affinity (ΔG = −8.4 kcal/mol), followed by quercetin (ΔG = −8.0 kcal/mol) and kaempferol (ΔG = −7.1 kcal/mol). Quercetin displayed the most conserved interaction pattern with the key ERβ residues Glu305, Arg346, and His475, whereas 3-carene-5-one achieved superior affinity through extensive hydrophobic interactions. ADMET prediction indicated that 3-carene-5-one possessed more favorable membrane permeability and metabolic characteristics, while quercetin and kaempferol demonstrated comparatively safer nephrotoxicity, neurotoxicity, and hepatotoxicity profiles. Conclusion: The integrated in silico analysis identified 3-carene-5-one, quercetin, and kaempferol as the most promising ERβ-targeting candidates from K. galanga. Among them, 3-carene-5-one emerged as the most promising lead candidate owing to its superior binding affinity and balanced pharmacokinetic properties, while quercetin exhibited the most native ligand-like binding interactions, supporting further experimental validation for the development of novel ERβ-targeted phytopharmaceuticals.