title: Computationally identified novel diphenyl- and phenylpyridine androgen receptor antagonist structures.
abstract: We have identified and profiled a set of androgen receptor (AR) binding compounds representing two nonsteroidal scaffolds from a public chemical database supplied by Asinex with virtual screening procedure incorporating our recently published 3D QSAR model of AR ligands. The diphenyl- and phenylpyridine-based compounds act as antagonists in wild-type AR in CV1 cells and also retain this antagonistic character in CV1 cells expressing T877A mutant receptor. This mutation is frequently associated with prostate cancer. Two of the compounds repress the androgen-dependent cell growth of LNCaP prostate cancer cells expressing the T877A AR mutant. Molecular modeling of the observed in vitro antagonism with induced fit docking suggests that W741 and M895 could be mechanistically involved in the initiation of the antagonism. The results indicate finding of nonsteroidal AR antagonist compounds from a public chemical database with computational methods. Compounds could serve as a novel platform to develop more potent AR antagonists with inhibitory activity in both wild-type and T877A mutant AR.
authors: CSC-Scientific Computing Ltd., PO Box 405, FI-02101 Espoo, Finland.
authors: Annu A
authors: AA
authors: Söderholm
authors: Johanna
authors: J
authors: Viiliäinen
authors: Pekka T
authors: PT
authors: Lehtovuori
authors: Hanna
authors: H
authors: Eskelinen
authors: Daniela
authors: D
authors: Roell
authors: Aria
authors: A
authors: Baniahmad
authors: Tommi H
authors: TH
authors: Nyrönen
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000813:Anilides / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D005485:Flutamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D014105:Tosyl Compounds / Q000737:chemistry
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D011725:Pyridines; D014105:Tosyl Compounds; C014290:hydroxyflutamide; D005485:Flutamide; C053541:bicalutamide