Experimental & Clinical Pharmacology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø- The Arctic University of Norway, 9037 Tromsø, Norway; Research Group in Pharmacology, Department of Pharmacy, Faculty of Health Sciences, University of Tromsø- The Arctic University of Norway, 9037 Tromsø, Norway.
Experimental & Clinical Pharmacology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø- The Arctic University of Norway, 9037 Tromsø, Norway.
Bioorg Med Chem. 2021 Apr 15;36:116060. doi: 10.1016/j.bmc.2021.116060. Epub 2021 Feb 20.
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.
雄性激素睾酮主要通过属于尿苷二磷酸（UDP）葡糖醛酸基转移酶（UGT）家族的肝酶代谢。这些酶是主要的第二期酶，它们在人类内源性和外源性化合物的解毒中起着重要作用。本研究旨在提高对 UGT2B17 结合特性的理解。使用同源建模程序根据具有已知晶体结构的模板生成 UGT2B17 酶的模型。进行抑制剂的分子对接，以进一步了解配体与结合位点之间的相互作用，并确定哪个模型具有最佳的准确性。ROC 曲线用于评估模型区分结合物（抑制剂）和非结合物（诱饵）的能力。在比较基于四个不同晶体结构的四个模型时，基于 4AMG 晶体结构的模型在区分真正的结合物和非结合物方面最为准确。研究药理学 UGT2B17 抑制可能为低睾酮水平的患者提供新的治疗方法。这种治疗方法可能会提高内源性睾酮水平，并提供更可预测的血清浓度升高，而不是通过直接用睾酮治疗产生非生理性的血清水平升高，这对制定可预测的治疗方案和降低严重不良反应的风险都有好处。本研究可作为寻找旨在提高睾酮水平的新型药物的工具。
