A Novel Bifunctional Hybrid Conjugate of 3-O-Methyl Ellagic Acid and Urolithin A via PEG₃ Linker: In Silico CDK2-Targeted Strategy for Lung Cancer Therapy

Abstract

Cyclin-dependent kinase 2 (CDK2) is a critical regulator of cell cycle progression and is frequently dysregulated in lung cancer, contributing to uncontrolled proliferation and tumor progression. In this study, a novel bifunctional hybrid conjugate of 3-O-methyl ellagic acid and urolithin A was rationally designed using a PEG₃ linker to evaluate its potential as a CDK2 inhibitor through computational docking approaches. The hybrid design integrates two bioactive pharmacophores: a methylated ellagic acid derivative with improved lipophilicity and a gut microbiota-derived metabolite known for anticancer properties. Molecular docking was performed against the ATP-binding pocket of CDK2, and results were compared with parent compounds and a standard inhibitor. The designed conjugate exhibited significantly improved binding affinity and multi-point interactions within the active site, involving key residues such as Leu83, Lys33, and Asp145. Hydrogen bonding, hydrophobic interactions, and π–π stacking collectively contributed to enhanced complex stability. The findings suggest that linker-based pharmacophore hybridization may serve as a promising strategy for developing novel CDK2-targeted anticancer agents.