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dc.contributor.authorSerçinoğlu, Onur
dc.contributor.authorBereketoğlu, Ceyhun
dc.contributor.authorOlsson, Per-Erik
dc.contributor.authorPradhan, Ajay
dc.date.accessioned2021-06-29T10:15:28Z
dc.date.available2021-06-29T10:15:28Z
dc.date.issued2021en_US
dc.identifier.citationSerçinoğlu, O., Bereketoglu, C., Olsson, P.-E., Pradhan, A. (2021). In silico and in vitro assessment of androgen receptor antagonists. Computational Biology and Chemistry, 92, art. no. 107490. https://doi.org/10.1016/j.compbiolchem.2021.107490en_US
dc.identifier.urihttps://doi.org/10.1016/j.compbiolchem.2021.107490
dc.identifier.urihttps://hdl.handle.net/20.500.12508/1797
dc.description.abstractThere is a growing concern for male reproductive health as studies suggest that there is a sharp increase in prostate cancer and other fertility related problems. Apart from lifestyle, pollutants are also known to negatively affect the reproductive system. In addition to many other compounds that have been shown to alter androgen signaling, several environmental pollutants are known to disrupt androgen signaling via binding to androgen receptor (AR) or indirectly affecting the androgen synthesis. We analyzed here the molecular mechanism of the interaction between the human AR Ligand Binding Domain (hAR-LBD) and two environmental pollutants, linuron (a herbicide) and procymidone (a pesticide), and compared with the steroid agonist dihydrotestosterone (DHT) and well-known hAR antagonists bicalutamide and enzalutamide. Using molecular docking and dynamics simulations, we showed that the co-activator interaction site of the hAR-LBD is disrupted in different ways by different ligands. Binding free energies of the ligands were also ordered in increasing order as follows: linuron, procymidone, DHT, bicalutamide, and enzalutamide. These data were confirmed by in vitro assays. Reporter assay with MDA-kb2 cells showed that linuron, procymidone, bicalutamide and enzalutamide can inhibit androgen mediated activation of luciferase activity. Gene expression analysis further showed that these compounds can inhibit the expression of prostate specific antigen (PSA) and microseminoprotein beta (MSMB) in prostate cell line LNCaP. Comparative analysis showed that procymidone is more potent than linuron in inhibiting AR activity. Furthermore, procymidone at 10 mu M dose showed equivalent and higher activity to AR inhibitor enzalutamide and bicalutamide respectively.en_US
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.relation.isversionof10.1016/j.compbiolchem.2021.107490en_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectHelix 12en_US
dc.subjectAntiandrogenen_US
dc.subjectProstateen_US
dc.subjectEndocrine disruptionen_US
dc.subjectPollutantsen_US
dc.subject.classificationMDV 3100
dc.subject.classificationAndrogen Receptors
dc.subject.classificationCastration
dc.subject.classificationBiology
dc.subject.classificationComputer Science
dc.subject.classificationInterdisciplinary Applications
dc.subject.otherAlters sexual-differentiation
dc.subject.otherReporter gene assays
dc.subject.otherMolecular-dynamics
dc.subject.otherMale-rat
dc.subject.otherRisk-assessment
dc.subject.otherRainbow-trout
dc.subject.otherLinuron
dc.subject.otherProcymidone
dc.subject.otherEndocrine
dc.subject.otherPesticides
dc.subject.otherAntigens
dc.subject.otherBinding energy
dc.subject.otherCell culture
dc.subject.otherDiseases
dc.subject.otherGene expression
dc.subject.otherPollution
dc.subject.otherUrology
dc.subject.otherAndrogen receptor antagonists
dc.subject.otherComparative analysis
dc.subject.otherEnvironmental pollutants
dc.subject.otherGene expression analysis
dc.subject.otherLigand binding domain
dc.subject.otherLuciferase activities
dc.subject.otherProstate specific antigen
dc.subject.otherReproductive systems
dc.subject.otherLigands
dc.titleIn silico and in vitro assessment of androgen receptor antagonistsen_US
dc.typearticleen_US
dc.relation.journalComputational Biology and Chemistryen_US
dc.contributor.departmentMühendislik ve Doğa Bilimleri Fakültesi -- Biyomedikal Mühendisliği Bölümüen_US
dc.identifier.volume92en_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.contributor.isteauthorBereketoğlu, Ceyhun
dc.relation.indexWeb of Science - Scopus - PubMeden_US
dc.relation.indexWeb of Science Core Collection - Science Citation Index Expanded


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