Phytoestrogens are dietary
estrogens having similar structure as of
estrogen. Some of these
phytoestrogens are
androgen receptor (AR) antagonists and exhibit preventive role in the
prostate cancer. However, in
androgen-independent
prostate cancer (
AIPC) the ARs were mutated (T877A, W741L, F876L, etc.) and these mutant ARs convert the antagonist to agonist. Our aim in this study is to find
phytoestrogens that could function as an antagonist with wild and mutant ARs. The
phytoestrogens were analyzed for binding affinity with wild and mutant ARs in agonist and antagonist conformations. The point mutations were carried out using Chimera. The antagonist AR conformation was modeled using Modeller. We hypothesize that the compounds having binding affinity with agonist AR conformation could not function as a full or pure antagonist. Most of the
phytoestrogens have binding affinity with agonist AR conformation contradicting previous results. For example,
genistein which is a widely studied
isoflavone has known AR antagonist property. However, in our study, it had good binding affinity with agonist AR conformation. Hence, to confirm our hypothesis, we tested
genistein in LNCaP (T877A mutant AR) cells by qPCR studies. The
genistein functioned as an antagonist only in the presence of an
androgen indicting a partial agonist type of activity. The in-vitro results supported our docking hypothesis. We applied this principle and found
syringaresinol could function as an antagonist with wild and mutated ARs. Further, we carried out molecular dynamics for the hit molecule to confirm its antagonist binding mode with mutant AR.Communicated by Ramaswamy H. Sarma.