Rauhamäki Sanna, Postila Pekka A, Lätti Sakari, Niinivehmas Sanna, Multamäki Elina, Liedl Klaus R, Pentikäinen Olli T
Department of Biological and Environmental Science & Nanoscience Center, University of Jyväskylä, P.O. Box 35, Jyväskylä FI-40014 University of Jyvaskyla, Finland.
Institute of Biomedicine, Integrative Physiology and Pharmacology, Kiinamyllynkatu 10 C6, University of Turku, FI-20520 Turku, Finland.
ACS Omega. 2018 Jun 30;3(6):6259-6266. doi: 10.1021/acsomega.8b00603. Epub 2018 Jun 11.
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 pIC 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.
维甲酸相关孤儿受体γt（RORγt）在辅助性T细胞17（TH17）细胞的分化中起着至关重要的作用。人们正在寻找强效且特异性的RORγt反向激动剂来治疗与TH17相关的疾病，如银屑病、类风湿性关节炎和1型糖尿病。在此，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，这两种计算机模拟技术提出的用于实验测试的化合物大多相同。总共，购买用于测试的34个分子中有11个被验证为RORγt反向激动剂，因此有效命中率为32%。这些化合物的pIC值从4.9（11 μM）到6.2（590 nM）不等。重要的是，经过验证的命中化合物代表四种不同的核心结构，这突出了RORγt反向激动作用的结构多样性以及所应用筛选方法促进药物设计中备受期待的骨架跃迁的能力。
