ArticleProceedings of the National Academy of Sciences of the United States of America2007
Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 100 citations in OpenAlex.
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- Revealing new therapeutic opportunities through drug target prediction: a class imbalance-tolerant machine learning approach.Bioinformatics (Oxford, England) · 2020Article
- Chemical Screening of Nuclear Receptor Modulators.International journal of molecular sciences · 2020Review
- Endocrine Disruption at the Androgen Receptor: Employing Molecular Dynamics and Docking for Improved Virtual Screening and Toxicity Prediction.International journal of molecular sciences · 2018Article
- 3D QSAR, pharmacophore and molecular docking studies of known inhibitors and designing of novel inhibitors for M18 aspartyl aminopeptidase of Plasmodium falciparum.BMC structural biology · 2016Article
- Repositioning organohalogen drugs: a case study for identification of potent B-Raf V600E inhibitors via docking and bioassay.Scientific reports · 2016Article
- Discriminating agonist and antagonist ligands of the nuclear receptors using 3D-pharmacophores.Journal of cheminformatics · 2016Article
- Androgen receptor: structure, role in prostate cancer and drug discovery.Acta pharmacologica Sinica · 2015Review
- Fluphenazine reduces proteotoxicity in C. elegans and mammalian models of alpha-1-antitrypsin deficiency.PloS one · 2014Article
- Ceftriaxone, an FDA-approved cephalosporin antibiotic, suppresses lung cancer growth by targeting Aurora B.Carcinogenesis · 2012Article
- ALiBERO: evolving a team of complementary pocket conformations rather than a single leader.Journal of chemical information and modeling · 2012Article
- Balancing target flexibility and target denaturation in computational fragment-based inhibitor discovery.Journal of computational chemistry · 2012Article
- FDA approved drugs complexed to their targets: evaluating pose prediction accuracy of docking protocols.Journal of molecular modeling · 2012Article
- Protein flexibility in docking and surface mapping.Quarterly reviews of biophysics · 2012Review
- Docking and scoring with ICM: the benchmarking results and strategies for improvement.Journal of computer-aided molecular design · 2012Article
- Core site-moiety maps reveal inhibitors and binding mechanisms of orthologous proteins by screening compound libraries.PloS one · 2012Article
- Compound activity prediction using models of binding pockets or ligand properties in 3D.Current topics in medicinal chemistry · 2012Review
- Structure-based systems biology for analyzing off-target binding.Current opinion in structural biology · 2011Review
- Small molecule inhibitors targeting the "achilles' heel" of androgen receptor activity.Cancer research · 2011Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.