Structure-Based Virtual Screening of Ultra-Large Library Yields Potent Antagonists for a Lipid GPCR
Michelson Center for Convergent Biosciences, Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA
Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC H3G 1Y6, Canada
Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich GmbH, 52425 Jülich, Germany
JuStruct: Jülich Center for Structural Biology, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Present address: MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
Biomolecules 2020, 10(12), 1634; https://doi.org/10.3390/biom10121634
Received: 29 October 2020 / Revised: 1 December 2020 / Accepted: 1 December 2020 / Published: 3 December 2020
(This article belongs to the Collection In Silico Drug Design for GPCRs: Big Data for Small Molecule Discovery)
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.