Detection of persistent organic pollutants binding modes with androgen receptor ligand binding domain by docking and molecular dynamics

Abstract

BackgroundPersistent organic pollutants (POPs) are persistent in the environment after release from industrial compounds, combustion productions or pesticides. The exposure of POPs has been related to various reproductive disturbances, such as reduced semen quality, testicular cancer, and imbalanced sex ratio. Among POPs, dichlorodiphenyldichloroethylene (4,4’-DDE) and polychlorinated biphenyls (PCBs) are the most widespread and well-studied compounds. Recent studies have revealed that 4,4’-DDE is an antagonist of androgen receptor (AR). However, the mechanism of the inhibition remains elusive. CB-153 is the most common congener of PCBs, while the action of CB-153 on AR is still under debate.ResultsMolecular docking and molecular dynamics (MD) approaches have been employed to study binding modes and inhibition mechanism of 4,4’-DDE and CB-153 against AR ligand binding domain (LBD). Several potential binding sites have been detected and analyzed. One possible binding site is the same binding site of AR natural ligand androgen 5α-dihydrotestosterone (DHT). Another one is on the ligand-dependent transcriptional activation function (AF2) region, which is crucial for the co-activators recruitment. Besides, a novel possible binding site was observed for POPs with low binding free energy with the receptor. Detailed interactions between ligands and the receptor have been represented. The disrupting mechanism of POPs against AR has also been discussed.ConclusionsPOPs disrupt the function of AR through binding to three possible biding sites on AR/LBD. One of them shares the same binding site of natural ligand of AR. Another one is on AF2 region. The third one is in a cleft near N-terminal of the receptor. Significantly, values of binding free energy of POPs with AR/LBD are comparable to that of natural ligand androgen DHT.

Prenatal exposure to endocrine disrupting chemicals and risk of being born small for gestational age: Pooled analysis of seven European birth cohorts

“…PCB metabolites are high-affinity ligands for the thyroid hormone transport protein transthyretin (Cheek et al, 1999). p,p'-DDE binds to the androgen receptor (Kelce et al, 1995;Xu et al, 2013), while PFOA promotes adipocyte differentiation as a peroxisome proliferator-activated receptor gamma (PPARγ) ligand (White et al, 2011;Yamamoto et al, 2015). Several studies in rats demonstrated the thyroid-disrupting effect of the pesticides DDT (Scollon et al, 2004) and HCB (Alvarez et al, 2005;van Raaij et al, 1993a;van Raaij et al, 1993b), as they decreased serum levels of thyroid hormones.…”

Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP)

“…Water molecules in 1BNA were removed, while hydrogen atoms were added. In order to allow the ligand to explore the whole conformational space, AutoGrid 4.2 was used to calculate docking area of a grid box of 70 Â 100 Â 110 with grid spacing of 0.4 Å, which is big enough to cover the whole DNA molecule as to make sure there is enough space to fit the receptor and also for free rotations of ligands [33]. Docking experiment consisting of 100 simulations was performed for each compound, which were ranked in order of increasing docking energies values and grouped in clusters of similar confirmation.…”

3D models of bisphenol A and its metabolite 4-methyl-2,4-bis (4-hydroxyphenyl)-pent-1-ene (MBP) antagonist binding to human progesterone receptor

“…However, antagonistic studies of BPA on some 39 . Other endocrine disruptors such as dichlorodiphenyldichloroethylene (4,4ʹ-DDE), which structure is very similar to BPA, was also illustrated to have endo crine disruption on human androgen receptor 40 . Although the simulation platforms and scoring functions were different, the results indicated that BPA and/or its analogues, had widely antagonist effects on nuclear receptors.…”