title: Molecular insight into the differential anti-androgenic activity of resveratrol and its natural analogs: in silico approach to understand biological actions.
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 exhibited strongest anti-androgenic activity and its binding energy and hydrogen bonding interactions pattern closely resembled 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 stilbenes.
authors.affiliation: Laboratory of Computational Biophysics & Bioengineering, Department of Physics, Tougaloo College, Tougaloo, MS 39174, USA. pbiswas@tougaloo.edu and Department of Physical Chemistry, Indian Association for the Cultivation of Science, Kolkata, India.
authors.forename: Sandipan
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39202, USA.
authors.forename: Avinash
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39202, USA and Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39202, USA.
authors.forename: Nasir A
authors.initials: NA
authors.lastname: Butt
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39202, USA.
authors.forename: Liangfen
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Laboratory of Computational Biophysics & Bioengineering, Department of Physics, Tougaloo College, Tougaloo, MS 39174, USA. pbiswas@tougaloo.edu.
authors.forename: Raquema
authors.initials: R
authors.lastname: Williams
authors.affiliation: United States Department of Agriculture, Agriculture Research Service, Natural Products Utilization Research Unit, University, MS 38677, USA.
authors.forename: Agnes M
authors.initials: AM
authors.lastname: Rimando
authors.affiliation: Laboratory of Computational Biophysics & Bioengineering, Department of Physics, Tougaloo College, Tougaloo, MS 39174, USA. pbiswas@tougaloo.edu.
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Biswas
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39202, USA and Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39202, USA.
authors.forename: Anait S
authors.initials: AS
authors.lastname: Levenson
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003198:Computer Simulation; D005485:Flutamide / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008297:Male; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D050505:Mutant Proteins; D011944:Receptors, Androgen; D013267:Stilbenes; C107773:pterostilbene; C041525:3,3',4,5'-tetrahydroxystilbene; D005485:Flutamide; D000077185:Resveratrol