Molecular insight into the differential anti-androgenic activity of resveratrol and its natural analogs: In Silico approach to understand biological actions

Authors: CHAKRABORTY, SANDIPAN - Tougaloo College; KUMAR, AVINASH - University Of Mississippi Medical Center; BUTT, NASIR - University Of Mississippi Medical Center; ZHANG, LIANGFEN - University Of Mississippi Medical Center; WILLIAMS, RAQUEMA - Tougaloo College; Rimando, Agnes; BISWAS, PRADIP - Tougaloo College; LEVENSON, ANAIT - University Of Mississippi Medical Center

Submitted to: Molecular Biosystems
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/5/2016
Publication Date: 4/11/2016
Publication URL: http://handle.nal.usda.gov/10113/62409
Citation: Chakraborty, S., Kumar, A., Butt, N.A., Zhang, L., Williams, R., Rimando, A.M., Biswas, P.K., Levenson, A.S. 2016. Molecular insight into the differential anti-androgenic activity of resveratrol and its natural analogs: In Silico approach to understand biological actions. Molecular Biosystems. 12:1702-1709. DOI: 10.1039/C6MB00186F

Interpretive Summary: The androgen receptor (AR) is a therapeutic target for the treatment of prostate cancer. Resveratrol, a well-known stilbenoid found in grapes and other fruits, and its natural analogs exhibit varying degrees of anti-androgenic effects on tumor growth suppression in prostate cancer. We studied the anti-androgenic activities of resveratrol and its natural analogs, namely, pterostilbene, piceatannol and trimethoxy-resveratrol in prostate cancer cells expressing mutant AR. We also performed atomistic simulations to study the relationship between chemical structure and anti-androgenic activity. Among the analogs, pterostilbene exhibited the strongest anti-androgenic activity and its binding energy and chemical bond interaction pattern closely resemble that of flutamide, a known snit-androgen that is used to treat prostate cancer. Our studies revealed that androgenic compounds bind more strongly to the active site of AR LBD compared to anti-androgenic compounds and provide stabilization of the receptor. The present study provides critical insight into the structure-activity relationship of the anti-androgenic action of resveratrol analogs, which can be utilized to make other novel anti-androgenic stilbenoids.

Technical Abstract: The androgen receptor (AR) is a therapeutic target for the treatment of prostate cancer. Androgen receptor reactivation during the androgen-independent stage of prostate cancer is mediated by numerous mechanisms including expression of AR mutants and splice variants that become non-responsive to conventional anti-androgenic agents. Resveratrol and its natural analogs exhibit varying degrees of anti-androgenic effects on tumor growth suppression in prostate cancer. However, the structural basis for the observed differential activity remains unknown. Here, anti-androgenic activities of resveratrol and its natural analogs, namely, pterostilbene, piceatannol and trimethoxy-resveratrol were studied in LNCaP cells expressing T877A mutant AR and atomistic simulations were employed to establish the structure activity relationship. Interestingly, essential hydrogen bonding contacts and the binding energies of resveratrol analogs with AR ligand binding domain (LBD), emerge as key differentiating factors for varying anti-androgenic action. Among all the analogs, pterostilbene exhibits strongest anti-androgenic activity and its binding energy and hydrogen bonding interactions pattern closely resemble pure anti-androgen, flutamide. Principal component analysis of our simulation studies revealed that androgenic compounds bind more strongly to AR LBD compared to anti-androgenic compounds and provide conformational stabilization of the receptor in essential subspace. The present study provides critical insight into the structure-activity relationship of the anti-androgenic action of resveratrol analogs, which can be translated further to design novel highly potent anti-androgenic stilbenoids.