Molecular dynamics simulations reveal the plausible agonism/antagonism mechanism by steroids on androgen receptor mutations

Androgen receptors (AR) are the primary drug target in prostate cancer (PCa). There are several drugs developed against its activity for prostate cancer treatment, but cancer cells revive AR signaling against those drugs by using alternative steroids such as glucocorticoids. In addition, antagonists become agonists due to emergence of mutations in AR gene. The mechanism by which antagonists are converted into agonists and how AR signaling is recovered by other steroids has yet to be fully elucidated. In this study, we interrogated the role of bicalutamide conformation in its antagonist function and how glucocorticoids such as prednisolone and dexamethasone revive AR signaling at the molecular level by means of molecular dynamics. We found that the ‘‘closed’’ conformation of bicalutamide is essential for its antagonist function and W741 residue is forcing it into this conformation. Moreover, we show that prednisolone and dexamethasone behave like natural agonist DHT which confirm the experimental results that show their role in the reviving AR signaling in the case of ARL701H mutation. [Display omitted] •The effect of clinical mutations on the AR signaling activity was computationally investigated.•The MD analysis suggest that the L701H mutation increase AR affinity to glucocorticoids.•The effect of mutations on the flexibility of helix-12 was correlated to agonist/antagonist behavior.•The conformational changes in bicalutamide towards acting as agonist or antagonist were revealed.