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BMC Structural Biology

, 13:16

Computational analysis

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.

KeywordsPersistent organic pollutants Androgen receptor Molecular docking Molecular dynamics MM-PBSA AbbreviationsPOPsPersistent organic pollutants

EDCsEndocrine disrupting chemicals

4,4’-DDEDichlorodiphenyldichloroethylene

PCBsPolychlorinated biphenyls

CB-1532,2’,4,4’,5,5’-Hexachlorobiphenyl

DHT5α-Dihydrotestosterone

NRNuclear receptor

ARAndrogen receptor

LBDLigand binding domain

AF2Activation function 2

PBSPotential binding site

MDMolecular dynamics

MM-PBSAMolecular mechanics-Poisson-Boltzmann surface area.

Electronic supplementary materialThe online version of this article doi:10.1186-1472-6807-13-16 contains supplementary material, which is available to authorized users.

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Autor: Xian Jin Xu - Ji Guo Su - Anna Rita Bizzarri - Salvatore Cannistraro - Ming Liu - Yi Zeng - Wei Zu Chen - Cun Xin Wan

Fuente: https://link.springer.com/







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