Syringaresinol as a novel androgen receptor antagonist against wild and mutant androgen receptors for the treatment of castration-resistant prostate cancer: molecular docking, in-vitro and molecular dynamics study.

Divakar Selvaraj, Santhoshkumar Muthu, Satvik Kotha, Ramachandra Setty Siddamsetty, Sasikumar Andavar, Saravanan Jayaraman

Journal of biomolecular structure & dynamics 2021 Feb

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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.

Citation

Divakar Selvaraj, Santhoshkumar Muthu, Satvik Kotha, Ramachandra Setty Siddamsetty, Sasikumar Andavar, Saravanan Jayaraman. Syringaresinol as a novel androgen receptor antagonist against wild and mutant androgen receptors for the treatment of castration-resistant prostate cancer: molecular docking, in-vitro and molecular dynamics study. Journal of biomolecular structure & dynamics. 2021 Feb;39(2):621-634