Identification of Pharmacophore for Wild and T877A Mutant Androgen Receptor Antagonist

Abstract

Androgen increases the proliferation of prostate cancer cells by activating the androgen receptor (AR). AR antagonists block the androgen mediated proliferation and are used to treat prostate cancer. Antagonist resistance occurs due to the expression of mutations in AR. One particular mutation, T877A, was frequently expressed in relapsed patients. Presently, there is no antagonist in the market without the problem of resistance developing over the period of treatment. A plausible reason for this shortcoming could be the lack of designing because of the unavailability of AR-crystal structure in antagonist bound conformation. Hence, 3D-QSAR becomes a major tool in identification of novel AR antagonists. Three models, ADDHRR.295, AHHRR.266, and AHRR.63 were designed for wild type, T877A mutant, and full (active at both wild and mutant types) AR antagonists respectively. There is a major difference in the angles and lengths of the pharmacophore site points among the 3D-QSAR models. The generated pharmacophore for full antagonists was then used for screening the SPECS database with filters for identifying hits.