title: Modeling androgen receptor flexibility: a binding mode hypothesis of CYP17 inhibitors/antiandrogens for prostate cancer therapy.
abstract: Prostate Cancer (PCa), a leading cause of cancer death worldwide (www.cancer.gov), is a complex malignancy where a spectrum of targets leads to a diversity of PCa forms. A widely pursued therapeutic target is the Androgen Receptor (AR). As a Steroid Hormone Receptor, AR serves as activator of transcription upon binding to androgens and plays a central role in the development of PCa. AR is a structurally flexible protein, and conformational plasticity of residues in the binding-pocket is a key to its ability to accommodate ligands from various chemical classes. Besides direct modulation of AR activity by antagonists, inhibition of cytochrome CYP17 (17α-hydroxylase/17,20-lyase), essential in androgen biosynthesis, has widely been considered an effective strategy against PCa. Interestingly, Handratta et al. (2005) discovered new, potent inhibitors of CYP17 (C-17 steroid derivatives) with pure AR antagonistic properties. Although the antiandrogenic activity of their lead compound (VN/124-1) has been experimentally proven both in vitro and in vivo, no structural data are currently available to elucidate the molecular determinants responsible for these desirable dual inhibitory properties. We implemented a Structure-based Drug Design (SBDD) approach to generate a valuable hypothesis as to the binding modes of steroidal CYP17 inhibitors/antiandrogens against the AR. To deal with the plasticity of residues buried in the Ligand Binding Domain (LBD), we developed a flexible-receptor Docking protocol based on Induced-Fit (IFD) methodology (www.schrodinger.com/). Our results constitute an ideal starting point for the rational design of next-generation analogues of CYP17 inhibitors/antiandrogens as well as an attractive tool to suggest novel chemical classes of AR antagonists.
authors.affiliation: Department of Chemistry & Biochemistry, University of the Sciences, 600 S. 43rd Street, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gianti
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Zauhar
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry*; D000730:Androstadienes / Q000737:chemistry*; D001562:Benzimidazoles / Q000737:chemistry*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D009154:Mutation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011944:Receptors, Androgen / Q000737:chemistry*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000737:chemistry; D013816:Thermodynamics
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000730:Androstadienes; D001562:Benzimidazoles; D011944:Receptors, Androgen; D013739:Testosterone; D013254:Steroid 17-alpha-Hydroxylase; C500627:3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene