title: Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs.
abstract: Finding good drug leads de novo from large chemical libraries, real or virtual, is not an easy task. High-throughput screening is often plagued by low hit rates and many leads that are toxic or exhibit poor bioavailability. Exploiting the secondary activity of marketed drugs, on the other hand, may help in generating drug leads that can be optimized for the observed side-effect target, while maintaining acceptable bioavailability and toxicity profiles. Here, we describe an efficient computational methodology to discover leads to a protein target from safe marketed drugs. We applied an in silico "drug repurposing" procedure for identification of nonsteroidal antagonists against the human androgen receptor (AR), using multiple predicted models of an antagonist-bound receptor. The library of marketed oral drugs was then docked into the best-performing models, and the 11 selected compounds with the highest docking score were tested in vitro for AR binding and antagonism of dihydrotestosterone-induced AR transactivation. The phenothiazine derivatives acetophenazine, fluphenazine, and periciazine, used clinically as antipsychotic drugs, were identified as weak AR antagonists. This in vitro biological activity correlated well with endocrine side effects observed in individuals taking these medications. Further computational optimization of phenothiazines, combined with in vitro screening, led to the identification of a nonsteroidal antiandrogen with improved AR antagonism and marked reduction in affinity for dopaminergic and serotonergic receptors that are the primary target of phenothiazine antipsychotics.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Bisson
authors.forename: A V
authors.initials: AV
authors.lastname: Cheltsov
authors.forename: N
authors.initials: N
authors.lastname: Bruey-Sedano
authors.forename: B
authors.initials: B
authors.lastname: Lin
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: N
authors.initials: N
authors.lastname: Goldberger
authors.forename: L T
authors.initials: LT
authors.lastname: May
authors.forename: A
authors.initials: A
authors.lastname: Christopoulos
authors.forename: J T
authors.initials: JT
authors.lastname: Dalton
authors.forename: P M
authors.initials: PM
authors.lastname: Sexton
authors.forename: X-K
authors.initials: XK
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Abagyan
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D004298:Dopamine / Q000378:metabolism; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010640:Phenothiazines / Q000737:chemistry; D017430:Prostate-Specific Antigen / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011944:Receptors, Androgen / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D004364:Pharmaceutical Preparations; D010640:Phenothiazines; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D012701:Serotonin; D017430:Prostate-Specific Antigen; D004298:Dopamine