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.
Highlights
Persistent organic pollutants (POPs) are persistent in the environment after release from industrial compounds, combustion productions or pesticides
Molecular docking POPs were docked to androgen receptor (AR)/ligand binding domain (LBD) based on crystal structure taken from Protein Data Bank (PDB) with PDB entry 1I37 [17]
Docking of POPs to AR/LBD DHT was redocked to AR/LBD with 100 independent runs and docking results were clustered according to the root mean square difference (RMS) with a cutoff value 0.2 nm
Summary
Persistent organic pollutants (POPs) are persistent in the environment after release from industrial compounds, combustion productions or pesticides. Persistent organic pollutants (POPs), mainly from industrial compounds, combustion productions or pesticides, widely exist in the environment and are considered to be potential endocrine disrupting chemicals (EDCs) [1,2,3]. These compounds are persistent in the environment after releasing and transported to human body mainly through contaminated foods [4]. Studies on other members of the NR superfamily, such as estrogen receptors (ER) and progesterone receptor (PR), revealed that the AF2 region on LBD is the binding site of some antagonists [20,21,22,23]. Another novel binding site, binding function 3 (BF3), on the LBD have been identified by a recent virtual screening study combined with biochemical assays and X-ray crystallography [24,25] (see Figure 2)
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