Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs.

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Bisson WH, Cheltsov AV, Bruey-Sedano N, Lin B, Chen J, Goldberger N, May LT, Christopoulos A, Dalton JT, Sexton PM, Zhang XK, Abagyan R

Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs.

Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):11927-32. Epub 2007 Jul 2.

PubMed ID
17606915 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
AcetophenazineAndrogen receptorProteinHumans
Unknown
Not AvailableDetails
Fluphenazine5-hydroxytryptamine receptor 2AProteinHumans
Unknown
Not AvailableDetails
Fluphenazine5-hydroxytryptamine receptor 2CProteinHumans
Unknown
Not AvailableDetails
FluphenazineAndrogen receptorProteinHumans
Unknown
Not AvailableDetails
PericiazineAndrogen receptorProteinHumans
Unknown
Not AvailableDetails
PhenothiazineAndrogen receptorProteinHumans
Unknown
Not AvailableDetails
Pharmaco-proteomics
DrugDrug GroupsGeneGene IDChangeInteractionChromosome
StanoloneIllicit InvestigationalKLK3354
increased		Dihydrotestosterone results in increased expression of KLK3 protein19q13.33