Combining Molecular Docking and Pharmacophore Models Predicts Ligand Binding of Endocrine-Disrupting Chemicals to Nuclear Receptors

Abstract

Nuclear receptors form a family of proteins capable of accommodating a wide variety of small molecules in their ligand binding domain, ranging from therapeutic compounds to endocrine-disrupting chemicals. The rapid identification of these compounds, especially within the latter category, is of paramount importance. Using data extracted from the CompTox Dashboard, an Environmental Protection Agency initiative, we assessed the effectiveness of a combination of molecular docking and pharmacophore models in identifying ligands binding to six nuclear receptors: androgen receptor, estrogen receptor alpha, estrogen receptor beta, glucocorticoid receptor, peroxisome proliferator-activated receptor gamma, and thyroid hormone receptor alpha. For each nuclear receptor, we selected a specifically designed and optimized in silico protocol that, in conjunction with experimental assays, can prioritize compounds for further evaluation to detect any potential toxicological concerns.