The Regulatory Mechanisms of Molecular Chirality to the Androgen Receptor

Abstract Chirality is a fundamental characteristic of biological systems and underpins the structural architecture of key biomolecules such as amino acids and sugars. Molecular chirality can profoundly influence drug efficacy, often diminishing activity or even eliciting toxic effects. The androgen receptor (AR), a member of the nuclear receptor superfamily, plays a pivotal role in prostate cancer progression. Its ligand-binding domain (AR-LBD) exhibits pronounced chiral discrimination, resulting in marked stereoselectivity among enantiomeric ligands in modulating AR activity. However, the atomic-level mechanisms by which chirality governs AR conformation and function remain poorly understood. In this study, we employed funnel metadynamics simulations to investigate the binding pathways and free energy landscapes of the (R)- and (S)-enantiomers with AR-LBD. Our results reveal that the (S)-enantiomer stabilizes a conformation highly similar to the DHT-bound active state of AR through hydrophobic packing and cooperative polar interactions, facilitating optimal positioning of H12 and maintaining a complete interface for coactivator binding. Conversely, the (R)-enantiomer with a bulky C-5 substituent disrupts the hydrophobic core of the ligand-binding pocket and induces abnormal polar interactions. Such structural perturbation destabilizes the H11–H12 loop and distorts the activation function-2 (AF2) interface, which weakens the binding capacity of coactivator peptides. These findings elucidate the atomistic basis of chiral-specific regulation of AR and offer mechanistic insights that could inform the rational design of enantiopure therapeutics and strategies to overcome resistance in AR-targeted prostate cancer treatments.