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.