Computational Assessment of Combination Therapy of Androgen Receptor-Targeting Compounds.

The ligand-binding domain of the androgen receptor (AR) is a target for drugs against prostate cancer and offers three distinct binding sites for small molecules. Drugs acting on the orthosteric hormone binding site suffer from resistance mechanisms that can, in the worst case, reverse their therapeutic effect. While many allosteric ligands targeting either the activation function-2 (AF-2) or the binding function-3 (BF-3) have been reported, their potential for simultaneous administration with currently prescribed antiandrogens was disregarded. Here, we report results of 60 μs molecular dynamics simulations to investigate combinations of orthosteric and allosteric AR antagonists. Our results suggest BF-3 inhibitors to be more suitable in combination with classical antiandrogens as opposed to AF-2 inhibitors based on binding free energies and binding modes. As a mechanistic explanation for these observations, we deduced a structural adaptation of helix-12 involved in the formation of the AF-2 site by classical AR antagonists. Additionally, the changes were accompanied by an expansion of the orthosteric binding site. Considering our predictions, the selective combination of AR-targeting compounds may improve the treatment of prostate cancer.