Introduction: Androgen receptor (AR) plays a pivotal role in the development of male
sex and contributes to prostate cancer growth. Different from other nuclear receptors that bind to
the co-regulator LxxLL motif in coregulator peptide interaction, the AR Ligand Binding Domain
(LBD) prefers to bind to the FxxLF motif. BUD31, a novel co-regulator with FxxLF motif, has
been demonstrated to suppress wild-type and mutated AR-mediated prostate cancer growth.
Methods: To find out the interaction mechanisms of BUD31 with WT/T877A/W741L AR complex,
molecular dynamics simulations were employed to study the complex BUD31 and
WT/mutant ARs. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) results
demonstrated that T877A and W741L point mutations can reduce the binding affinity between
BUD31 and AR. The RMSF and dynamic cross-correlation analysis indicated that amino acid point
mutations can affect the motions of loop residues in the AR structure.
Results: These results indicated that AR co-regulator binding site AF2 can serve as a target for
drug discovery to solve the resistance problem.