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.

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靶向核受体药物的计算研究

内分泌干​​扰化学物质已被证明会在激素合成、转运、代谢、结合、作用和消除水平上干扰内分泌系统功能。它们与人类的多种健康问题有关：肥胖、糖尿病、不孕症、甲状腺和神经内分泌功能受损、神经发育问题和癌症等。由于药物是人类经常接触较长时间的化学物质，因此应特别强调其干扰内分泌的潜力。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 评估了对 12 种核受体的结合亲和力。我们鉴定了 130 种对核受体具有高结合亲和力的药物，而核受体不是其药理学靶点。在对具有内分泌干扰组的核受体具有高结合亲和力的一组药物中，使用另一个分子对接程序 VirtualToxLab 获得的计算机模拟结果进行评估时，阳性预测值为 0.66，而使用 Tox21 的体外结果进行评估时，阳性预测值为 0.32数据库。计算筛选被证明在优先考虑用于体外测试的药物方面是有用的。我们建议进一步研究药物与此处预测的核受体的新相互作用。使用另一个分子对接程序 VirtualToxLab 获得的计算机模拟结果进行评估时，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。计算筛选被证明在优先考虑用于体外测试的药物方面是有用的。我们建议进一步研究药物与此处预测的核受体的新相互作用。使用另一个分子对接程序 VirtualToxLab 获得的计算机模拟结果进行评估时，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。计算筛选被证明在优先考虑用于体外测试的药物方面是有用的。我们建议进一步研究药物与此处预测的核受体的新相互作用。