期刊
BIOMOLECULES
卷 10, 期 12, 页码 -出版社
MDPI
DOI: 10.3390/biom10121634
关键词
structure-based lead discovery; virtual ligand screening; GPCR; cysteinyl leukotriene; CysLT receptors; asthma; uveal melanoma
资金
- University of Southern California
- Canadian Institutes of Health Research [FDN-148413]
- Institut de Pharmacologie de Sherbrooke (IPS)
- Centre d'excellence en neurosciences de l'Universite de Sherbrooke (CNS)
- Canadian Institutes of Health Research (CIHR)
- Fonds de Recherche en Sante du Quebec (FRQ-S)
- Ministry of Science and Higher Education of the Russian Federation [075-00337-20-03, FSMG -2020-0003]
- Russian Science Foundation [19-14-00261]
- Russian Science Foundation [19-14-00261] Funding Source: Russian Science Foundation
Cysteinyl leukotriene G protein-coupled receptors, CysLT1R and CysLT2R, regulate bronchoconstrictive and pro-inflammatory effects and play a key role in allergic disorders, cardiovascular diseases, and cancer. CysLT1R antagonists have been widely used to treat asthma disorders, while CysLT2R is a potential target against uveal melanoma. However, very few selective antagonist chemotypes for CysLT receptors are available, and the design of such ligands has proved to be challenging. To overcome this obstacle, we took advantage of recently solved crystal structures of CysLT receptors and an ultra-large Enamine REAL library, representing a chemical space of 680 M readily available compounds. Virtual ligand screening employed 4D docking models comprising crystal structures of CysLT1R and CysLT2R and their corresponding ligand-optimized models. Functional assessment of the candidate hits yielded discovery of five novel antagonist chemotypes with sub-micromolar potencies and the best Ki = 220 nM at CysLT1R. One of the hits showed inverse agonism at the L129Q constitutively active mutant of CysLT2R, with potential utility against uveal melanoma.
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