Modelling Biding Affinity of Steroids to Zebrafish Sex Hormone Binding Globulin

Abstract

The circulating endogenous steroids bound to a highly specific sex hormone-binding globulin (SHBG) and in lower-affinity to the proteins like the corticosteroid-binding protein and albumin in vertebrate including fish are transported in the bloodstream. 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 impact the normal activity of natural steroids. Because the xenobiotics are primarily released in the aquatic environment, there is a need to evaluate the binding affinity of xenosteroid mimics on fish SHBG, especially on zebrafish (Danio rerio), a small freshwater fish originating from India, which is widely used in ecotoxicology, toxicology, and genetics. Hence a zebrafish SHBG (zfSHBG) homology model was developed using human SHBG (hSHBG) receptor structure. It was shown that the interactions with amino acids viz. Ser-36, Asp-59 and Thr-54 were important for binding affinity. This model in addition to the HipHop based pharmacophore model well differentiated between zebrafish binders and non binders. Our study provide insights into the mechanism of action of endocrine disruptors in the zebrafish as well as a useful tool to identify anthropogenic compounds inhibiting zfSHBG.