Faculty of Pharmacy; University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia.
Molecules. 2020 Apr 1;25(7):1616. doi: 10.3390/molecules25071616.
Endocrine-disrupting chemicals have been shown to interfere with the endocrine system function at the level of hormone synthesis, transport, metabolism, binding, action, and elimination. They are associated with several health problems in humans: obesity, diabetes mellitus, infertility, impaired thyroid and neuroendocrine functions, neurodevelopmental problems, and cancer are among them. As drugs are chemicals humans can be frequently exposed to for longer periods of time, special emphasis should be put on their endocrine-disrupting potential. In this study, we conducted a screen of 1046 US-approved and marketed small-molecule drugs (molecular weight between 60 and 600) for estimating their endocrine-disrupting properties. Binding affinity to 12 nuclear receptors was assessed with a molecular-docking program, Endocrine Disruptome. We identified 130 drugs with a high binding affinity to a nuclear receptor that is not their pharmacological target. In a subset of drugs with predicted high binding affinities to a nuclear receptor with Endocrine Disruptome, the positive predictive value was 0.66 when evaluated with in silico results obtained with another molecular docking program, VirtualToxLab, and 0.32 when evaluated with in vitro results from the Tox21 database. Computational screening was proven useful in prioritizing drugs for in vitro testing. We suggest that the novel interactions of drugs with nuclear receptors predicted here are further investigated.
环境内分泌干扰物已被证明会在激素合成、运输、代谢、结合、作用和消除等水平上干扰内分泌系统功能。它们与人类的许多健康问题有关：肥胖、糖尿病、不孕、甲状腺和神经内分泌功能受损、神经发育问题和癌症等。由于药物是人类可以长时间频繁接触的化学物质，因此应特别强调其内分泌干扰潜力。在这项研究中，我们对 1046 种美国批准和上市的小分子药物（分子量在 60 到 600 之间）进行了筛选，以评估它们的内分泌干扰特性。使用分子对接程序 Endocrine Disruptome 评估了它们与 12 种核受体的结合亲和力。我们确定了 130 种与非药物靶点核受体具有高结合亲和力的药物。在具有预测的高核受体结合亲和力的药物亚集中，使用另一种分子对接程序 VirtualToxLab 获得的计算结果进行评估时，Endocrine Disruptome 的阳性预测值为 0.66，而使用 Tox21 数据库的体外结果进行评估时，阳性预测值为 0.32。计算筛选被证明可用于优先考虑药物进行体外测试。我们建议进一步研究此处预测的药物与核受体的新相互作用。
