title: Modelling the binding affinity of steroids to zebrafish sex hormone-binding globulin.
abstract: The circulating endogenous steroids are transported in the bloodstream. These are bound to a highly specific sex hormone-binding globulin (SHBG) and in lower affinity to proteins such as the corticosteroid-binding protein and albumin in vertebrates, including fish. It is generally believed that the glycoprotein SHBG protects these steroids from rapid metabolic degradation and thus intervenes in its availability at the target tissues. Endocrine disrupters binding to SHBG affect the normal activity of natural steroids. Since xenobiotics are primarily released in the aquatic environment, there is a need to evaluate the binding affinity of xenosteroid mimics on fish SHBG, especially in zebrafish (Danio rerio), a small freshwater fish originating in India and widely employed in ecotoxicology, toxicology, and genetics. In this context, a zebrafish SHBG (zfSHBG) homology model was developed using the human SHBG (hSHBG) receptor structure as template. It was shown that interactions with amino acids Ser-36, Asp-59 and Thr-54 were important for binding affinity. A ligand-based pharmacophore model was also developed for both zfSHBG and hSHBG inhibitors that differentiated binders from non-binders, but also demonstrated structural requirements for zfSHBG and hSHBG ligands. The study provides insights into the mechanism of action of endocrine disruptors in zebrafish as well as providing a useful tool for identifying anthropogenic compounds inhibiting zfSHBG.
authors.affiliation: a MPC Division , CSIR-CDRI , Lucknow , India.
authors.forename: A K
authors.initials: AK
authors.lastname: Saxena
authors.forename: J
authors.initials: J
authors.lastname: Devillers
authors.forename: A R R
authors.initials: AR
authors.lastname: Pery
authors.forename: R
authors.initials: R
authors.lastname: Beaudouin
authors.forename: V M
authors.initials: VM
authors.lastname: Balaramnavar
authors.forename: S
authors.initials: S
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D052244:Endocrine Disruptors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism*; D014874:Water Pollutants, Chemical / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D015262:Xenobiotics / Q000378:metabolism* / Q000633:toxicity; D015027:Zebrafish
chemical_list: D052244:Endocrine Disruptors; D012738:Sex Hormone-Binding Globulin; D014874:Water Pollutants, Chemical; D015262:Xenobiotics
keywords: Danio rerio; ecotoxicology; homology modelling; molecular docking; pharmacophore modelling; zebrafish SHBG