Molecular modeling study of the testosterone metabolizing enzyme UDP-glucuronosyltransferase 2B17

The dominant sex hormone testosterone is mainly metabolized by liver enzymes belonging to the uridine-diphospho (UDP) glucuronosyltransferase (UGT) family. These enzymes are the main phase II enzymes, and they have an important role in the detoxification of endogenous and exogenous compounds in humans. The aim of the present study was to improve the understanding of the binding properties of UGT2B17. A homology modelling procedure was used to generate models of the UGT2B17 enzyme based on templates with known crystal structures. Molecular docking of inhibitors was performed to gain further insights in the interactions between ligand and binding site, and to determine which of the models had the best accuracy. ROC curves were made to evaluate the ability of the models to differentiate between binders (inhibitors) and non-binders (decoys). When comparing the four models, which were based on four different crystal structures, the model based on the 4AMG crystal structure was the most accurate in distinguishing between true binders and non-binders. Investigating pharmacological UGT2B17 inhibition may provide novel treatment for patients with low testosterone levels. Such treatment may elevate endogenous testosterone levels and provide a more predictable increase in serum concentrations rather than un-physiological elevation of serum levels through direct treatment with testosterone, and this could be favorable both for giving a predictable treatment regime with reduced chances of serious adverse effects. The present study may serve as a tool in the search for novel drugs aiming for increasing testosterone levels

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

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

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

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