In Silico and In Vitro Investigation of the Piperineʼs 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.

Reversible Anti-Spermatogenic Effect of Piperine on Epididymis and Seminal Vesicles of Albino Rats

“…Chinta G, Periyasamy L. Anti-spermatogenic Effect of Piperine … Drug Res 2016; 66: 420-426 methacin, isoniazid, ethambutol, phenobarbitone, phenytoin, dapsone and ciprofloxacin [27][28][29]. Based on the positive modulation of bioavailability properties of piperine on anti-tubercular drugs like isoniazid and rifampicin, synergistically active formulations are available for clinical use in India since 2009 [8]. More interestingly, a literature survey completed in 2006 also reported that, catpiperine from the species of Piper longum and Piper nigrum possess the male contraceptive properties [3].…”

“…Trikatu, an Ayurvedic formulation containing black pepper and long pep-per as its ingredients were utilized for inducing the menstruation in the process of abortion [7]. Piperine is an active constituent present in Piper nigrum(black pepper) and Piper longum (long pepper), and is responsible for the pungency of these herbs [8]. Animal studies proved the effectiveness of piperine in treating various disorders like cognitive difficulties and depression [9][10][11].…”

“…This occurred due to the piperine's potential to decrease the spermatogenesis by reducing the production of testosterone or by decreasing its concentration in spermatogenic cells [44]. It also may be due to the disruption of spermatogenesis via piperiene's interaction with the active site of the androgen binding protein (ABP), which maintains the optimal level of the testosterone for the spermatogenesis [8]. However, there is no reduction was observed in the group (E7D) treated with the piperine at 10 mg/kg on every 7 th day.…”

Reversible testicular toxicity of piperine on male albino rats

“…Piperine is responsible for the pungency of both the herbs. [ 4 ] A formulation containing these two herbs as active ingredients was employed for inducing menstruation and as abortifacient in Indian traditional medicine. [ 5 ] Preclinical studies revealed the effectiveness of piperine in treating ailments such as neuronal difficulties and depression.…”

“…[ 24 25 26 ] Based on bioenhancing properties of piperine on antitubercular drugs such as isoniazid and rifampicin, synergistically acting formulations are available for clinical use in India since 2009. [ 4 ] A recent survey suggests that piperine is one among the 108 plant active constituents reported to have anti-fertility activity. [ 27 ] Furthermore, recent studies have proven the anti-fertility activity of piperine on male albino rats after 30 days of treatment.…”