title: Drug-Discovery Pipeline for Novel Inhibitors of the Androgen Receptor.
abstract: The androgen receptor (AR) is an important regulator of genes responsible for the development and recurrence of prostate cancer. Current therapies for this disease rely on small-molecule inhibitors that block the transcriptional activity of the AR. Recently, major advances in the development of novel AR inhibitors resulted from X-ray crystallographic information on the receptor and utilization of in silico drug design synergized with rigorous experimental testing.Herein, we describe a drug-discovery pipeline for in silico screening for small molecules that target an allosteric region on the AR termed the binding-function 3 (BF3) site. Following the identification of potential candidates, the compounds are tested in cell culture and biochemical assays for their ability to interact with and inhibit the AR. The described pipeline is readily accessible and could be applied in drug design efforts toward any surface-exposed region on the AR or other related steroid nuclear receptor.
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC, Canada, V6H 3Z6.
authors.forename: Kush
authors.initials: K
authors.lastname: Dalal
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC, Canada, V6H 3Z6.
authors.forename: Ravi
authors.initials: R
authors.lastname: Munuganti
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC, Canada, V6H 3Z6.
authors.forename: Hélène
authors.initials: H
authors.lastname: Morin
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC, Canada, V6H 3Z6.
authors.forename: Nada
authors.initials: N
authors.lastname: Lallous
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC, Canada, V6H 3Z6.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC, Canada, V6H 3Z6. acherkasov@prostatecentre.com.
authors.forename: Artem
authors.initials: A
authors.lastname: Cherkasov
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D019295:Computational Biology / Q000379:methods*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011487:Protein Conformation; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: Androgen receptor; Computer-aided drug design; Prostate cancer; Virtual screening