An insight about the mechanism of action (MoA) of R-bicalutamide on the androgen receptor homodimer using molecular dynamic

R-bicalutamide is a first-line therapy used to treat prostate cancer (PCa) inhibiting the androgen receptor (AR) which plays an important role in the development and the progression of PCa. However, after a protracted drug administration, many patients develop a form of androgen insensitivity since R-bicalutamide starts to exhibit some agonistic properties lead by the W741L AR mutation in the ligand-binding pocket even if the mechanism of the antagonist-agonist switch is still not clear. To study the drug-resistant mechanism, we explored the structural effects of the antagonist R-bicalutamide on the homodimer stability considering both the AR wild-type and W741L employing molecular dynamic (MD) simulations. The results obtained indicate that the binding of Rbicalutamide in the two AR monomers induces a great instability in the homodimer, which may determine the monomer's dissociation preventing AR migration into the nucleus and avoiding the transcriptional activity. If the W741L mutation occurs, the homodimer tends to have a behaviour close to the agonistic system where the two monomers are tightly bound, which may explain the effect of the W741L in drug insensitivity from a structural point of view.