Molecular modelling of the androgen metabolising enzyme UDP-glucuronosyltransferase 2B17

Abstract

The enzyme UDP-glucuronosyltransferase 2B17 (UGT2B17) has a major role in androgen metabolism, being involved in the conjugation of both testosterone and its potent metabolite dihydrotestosterone. The enzyme catalyses the transfer of glucuronic acid from UDP-glucuronic acid to the lipophilic androgen substrate. As a consequence, the water solubility of the substrate is increased, and it is more easily excreted from the body. Testosterone levels are important for male fertility and vitality, and are at their highest during adolescence and early adulthood. As some men get older their testosterone levels gradually decline. Other factors that can affect the levels are nutrients, exercise, lifestyle factors, drugs and endocrine disruptors. Inhibitors of the UGT2B17 could help maintain normal testosterone levels in patients with declining levels caused by various factors. Homology modelling is an in silico approach used to predict the 3D structure of an unknown protein structure, based on evolutionary related templates. An experimentally determined crystal structure of UGT2B17 had not been solved at the time of this study, consequently four homology models were constructed and refined using ICM. Molecular docking of inhibitors and decoys on the models was performed to gain insights in the interactions between ligand and binding site. Five residues in the binding pocket were proposed for future site-directed mutagenesis studies. The ability of the models to discriminate between inhibitors and decoys was evaluated using receiver operating characteristics curves, and the most accurate model was studied further with virtual ligand screening (VLS). Model_4AMG was identified as the most accurate, and VLS was performed on the model to screen structures from a chemical database for potential hit compounds. A hitlist of 25 compounds were identified as potential drug candidates, pending future in vitro testing to determine their binding affinity for UGT2B17.