Article

New aryl hydrocarbon receptor homology model targeted to improve docking reliability.

Dipartimento di Scienze dell'Ambiente e del Territorio, Università degli Studi di Milano-Bicocca, Piazza della Scienza 1, 20126 Milano, Italy.
Journal of Chemical Information and Modeling (impact factor: 4.68). 11/2011; 51(11):2868-81. DOI:10.1021/ci2001617 pp.2868-81
Source: PubMed

ABSTRACT The aryl hydrocarbon receptor (AhR) is a ligand-dependent, basic helix-loop-helix Per-ARNT-Sim (PAS) containing transcription factor that can bind and be activated by structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). As no experimentally determined structures of the AhR ligand binding domain (LBD) are available and previous homology models were only derived from apo template structures, we developed a new model based on holo X-ray structures of the hypoxia-inducible factor 2α (HIF-2α) PAS B domain, targeted to improve the accuracy of the binding site for molecular docking applications. We experimentally confirmed the ability of two HIF-2α crystallographic ligands to bind to the mAhR with relatively high affinity and demonstrated that they are AhR agonists, thus justifying the use of the holo HIF-2α structures as templates. A specific modeling/docking approach was proposed to predict the binding modes of AhR ligands in the modeled LBD. It was validated by comparison of the calculated and the experimental binding affinities of active THS ligands and TCDD for the mAhR and by functional activity analysis using several mAhR mutants generated on the basis of the modeling results. Finally the ability of the proposed approach to reproduce the different affinities of TCDD for AhRs of different species was confirmed, and a first test of its reliability in virtual screening is carried out by analyzing the correlation between the calculated and experimental binding affinities of a set of 14 PCDDs.

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Keywords

active THS ligands
 
AhR ligand binding domain
 
AhR ligands
 
aryl hydrocarbon receptor
 
basic helix-loop-helix Per-ARNT-Sim
 
binding site
 
different affinities
 
different species
 
experimental binding affinities
 
experimentally determined structures
 
functional activity analysis
 
HIF-2α crystallographic ligands
 
mAhR mutants
 
modeled LBD
 
modeling results
 
new model
 
previous homology models
 
specific modeling/docking approach
 
structurally diverse chemicals
 
toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin