Modelling the interaction of steroid receptors with endocrine disrupting chemicals.
BACKGROUND
The organic polychlorinated compounds like dichlorodiphenyltrichloroethane with its metabolites and polychlorinated biphenyls are a class of highly persistent environmental contaminants. They have been recognized to have detrimental health effects both on wildlife and humans acting as endocrine disrupters due to their ability of mimicking the action of the steroid hormones, and thus interfering with hormone response. There are several experimental evidences that they bind and activate human steroid receptors. However, despite the growing concern about the toxicological activity of endocrine disrupters, molecular data of the interaction of these compounds with biological targets are still lacking.


RESULTS
We have used a flexible docking approach to characterize the molecular interaction of seven endocrine disrupting chemicals with estrogen, progesterone and androgen receptors in the ligand-binding domain. All ligands docked in the buried hydrophobic cavity corresponding to the hormone steroid pocket. The interaction was characterized by multiple hydrophobic contacts involving a different number of residues facing the binding pocket, depending on ligands orientation. The EDC ligands did not display a unique binding mode, probably due to their lipophilicity and flexibility, which conferred them a great adaptability into the hydrophobic and large binding pocket of steroid receptors.


CONCLUSIONS
Our results are in agreement with toxicological data on binding and allow to describe a pattern of interactions for a group of ECD to steroid receptors suggesting the requirement of a hydrophobic cavity to accommodate these chlorine carrying compounds. Although the affinity is lower than for hormones, their action can be brought about by a possible synergistic effect.
D'Ursi
Pasqualina
P
Department of Biomedical Sciences and Technologies, University of Milan, Segrate, Milan, 20090, Italy. pasqualina.dursi@itb.cnr.it
Salvi
Erika
E
Fossa
Paola
P
Milanesi
Luciano
L
Rovida
Ermanna
E
D000595:Amino Acid Sequence; D001665:Binding Sites; D002713:Chlorine / Q000737:chemistry; D030562:Databases, Protein; D004347:Drug Interactions; D004702:Endocrine Glands / Q000378:metabolism; D004703:Endocrine System / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000737:chemistry; D006728:Hormones / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011987:Receptors, Steroid / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D012984:Software; D013256:Steroids / Q000378:metabolism
D047628:Estrogen Receptor alpha; D006728:Hormones; D008024:Ligands; D011987:Receptors, Steroid; D013256:Steroids; D002713:Chlorine