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ACS Omega. 2018 Jun 30;3(6):6259-6266. doi: 10.1021/acsomega.8b00603. Epub 2018 Jun 11.

Discovery of Retinoic Acid-Related Orphan Receptor γt Inverse Agonists via Docking and Negative Image-Based Screening.

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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.
Institute of General, Inorganic and Theoretical Chemistry, Centre for Chemistry and Biomedicine, University of Innsbruck, Innrain 82, A-6020 Innsbruck, Austria.


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.

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