Small molecules targeting the disordered transactivation domain of the androgen receptor induce the formation of collapsed helical states.

ABSTRACT: Intrinsically disordered proteins, which do not adopt well-defined structures under physiological conditions, are implicated in many human diseases. Small molecules that target the disordered transactivation domain of the androgen receptor have entered human trials for the treatment of castration-resistant prostate cancer (CRPC), but no structural or mechanistic rationale exists to explain their inhibition mechanisms or relative potencies. Here, we utilize all-atom molecular dynamics computer simulations to elucidate atomically detailed binding mechanisms of the compounds EPI-002 and EPI-7170 to the androgen receptor. Our simulations reveal that both compounds bind at the interface of two transiently helical regions and induce the formation of partially folded collapsed helical states. We

SUBMITTER: Zhu J 

PROVIDER: S-EPMC9613762 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature