Retinoic acid-related orphan receptor γt (RORγt) has a vital role in the differentiation of T-helper 17 (TH17) cells. Potent and specific RORγt inverse agonists are sought for treating TH17-related diseases such as psoriasis, rheumatoid arthritis, and type 1 diabetes. Here, the aim was to discover novel RORγt ligands using both standard molecular docking and negative image-based screening. Interestingly, both of these in silico techniques put forward mostly the same compounds for experimental testing. In total, 11 of the 34 molecules purchased for testing were verified as RORγt inverse agonists, thus making the effective hit rate 32%. The pIC₅₀ values for the compounds varied from 4.9 (11 μM) to 6.2 (590 nM). Importantly, the fact that the verified hits represent four different cores highlights the structural diversity of the RORγt inverse agonism and the ability of the applied screening methodologies to facilitate much-desired scaffold hopping for drug design.

中文翻译：

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通过对接和基于负图像的筛选发现与维甲酸相关的孤儿受体γt反向激动剂

维甲酸相关的孤儿受体γt（RORγt）在T辅助17（TH17）细胞的分化中起着至关重要的作用。寻找有效和特异性的RORγt反向激动剂来治疗与TH17相关的疾病，例如牛皮癣，类风湿性关节炎和1型糖尿病。在这里，目的是使用标准分子对接和基于负像的筛选来发现新型RORγt配体。有趣的是，这两种计算机技术都为实验测试提出了大多数相同的化合物。总共购买了用于测试的34个分子中的11个，被确认为RORγt反向激动剂，因此有效命中率达到32％。pIC ₅₀化合物的值从4.9（11μM）到6.2（590 nM）不等。重要的是，经过验证的命中代表了四个不同的核心，这一事实突显了RORγt反向激动剂的结构多样性以及所应用的筛选方法促进药物设计所急需的支架跳跃的能力。