Secondary Binding Site of CYP17A1 in Enhanced Sampling Simulations

Androgens like testosterone and dihydrotestosterone play a key role in prostate cancer progression, making the enzyme CYP17A1, essential for androgen synthesis, a crucial therapeutic target. Recent studies have revealed electron density at the substrate entry channel, suggesting the presence of a secondary binding site. In this study, we calculated the binding free energy landscape of known ligands at this site using Funnel Metadynamics. Our results characterize this binding site and indicate that nonheme-interacting ligands could effectively bind to CYP17A1, providing a novel approach to the design of CYP17A1 inhibitors.