Molecular modeling study of the testosterone metabolizing enzyme UDP-glucuronosyltransferase 2B17
| Autor: | Aina Westrheim Ravna, Georg Sager, Ingmar Trane, Erik Sveberg Dietrichs |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Glucuronosyltransferase Molecular model Clinical Biochemistry Pharmaceutical Science Endogeny 01 natural sciences Biochemistry Minor Histocompatibility Antigens Sex hormone-binding globulin Drug Discovery Humans Testosterone Binding site Enzyme Inhibitors Molecular Biology chemistry.chemical_classification biology Molecular Structure 010405 organic chemistry Organic Chemistry Testosterone (patch) VDP::Medisinske Fag: 700::Basale medisinske odontologiske og veterinærmedisinske fag: 710 Ligand (biochemistry) VDP::Medical disciplines: 700::Basic medical dental and veterinary science disciplines: 710 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Enzyme chemistry biology.protein Molecular Medicine |
| Zdroj: | Bioorganicmedicinal chemistry. 36 |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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