title: In Silico and In Vitro Investigation of the Piperine's Male Contraceptive Effect: Docking and Molecular Dynamics Simulation Studies in Androgen-Binding Protein and Androgen Receptor.
abstract: Understanding the molecular mechanism of action of traditional medicines is an important step towards developing marketable drugs from them. Piperine, an active constituent present in the Piper species, is used extensively in Ayurvedic medicines (practiced on the Indian subcontinent). Among others, piperine is known to possess a male contraceptive effect; however, the molecular mechanism of action for this effect is not very clear. In this regard, detailed docking and molecular dynamics simulation studies of piperine with the androgen-binding protein and androgen receptors were carried out. Androgen receptors control male sexual behavior and fertility, while the androgen-binding protein binds testosterone and maintains its concentration at optimal levels to stimulate spermatogenesis in the testis. It was found that piperine docks to the androgen-binding protein, similar to dihydrotestosterone, and to androgen receptors, similar to cyproterone acetate (antagonist). Also, the piperine-androgen-binding protein and piperine-androgen receptors interactions were found to be stable throughout 30 ns of molecular dynamics simulation. Further, two independent simulations for 10 ns each also confirmed the stability of these interactions. Detailed analysis of the piperine-androgen-binding protein interactions shows that piperine interacts with Ser42 of the androgen-binding protein and could block the binding with its natural ligands dihydrotestosterone/testosterone. Moreover, piperine interacts with Thr577 of the androgen receptors in a manner similar to the antagonist cyproterone acetate. Based on the in silico results, piperine was tested in the MDA-kb2 cell line using the luciferase reporter gene assay and was found to antagonize the effect of dihydrotestosterone at nanomolar concentrations. Further detailed biochemical experiments could help to develop piperine as an effective male contraceptive agent in the future.
authors.affiliation: Interdisciplinary Program in Life Sciences, Pondicherry University, Kalapet, Puducherry, India.
authors.forename: Gopichand
authors.initials: G
authors.lastname: Chinta
authors.affiliation: Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry, India.
authors.forename: Mariasoosai
authors.initials: M
authors.lastname: Ramya Chandar Charles
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Klopčič
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Marija
authors.initials: M
authors.lastname: Sollner Dolenc
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Kalapet, Puducherry, India.
authors.forename: Latha
authors.initials: L
authors.lastname: Periyasamy
authors.affiliation: Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry, India.
authors.forename: Mohane
authors.initials: M
authors.lastname: Selvaraj Coumar
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000727:Androgen-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D052117:Benzodioxoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020134:Catalytic Domain; D002460:Cell Line / Q000187:drug effects; D003198:Computer Simulation; D003272:Contraceptive Agents, Male / Q000737:chemistry / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008297:Male; D015741:Metribolone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000470:Alkaloids; D000727:Androgen-Binding Protein; D052117:Benzodioxoles; D003272:Contraceptive Agents, Male; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D015741:Metribolone; D012694:Serine; C008922:piperine