Structure-Based Virtual Screening of Ultra-Large Library Yields Potent Antagonists for a Lipid GPCR
Arman A. Sadybekov,
Rebecca L. Brouillette,
Egor Marin,
Anastasiia V. Sadybekov,
Aleksandra Luginina,
Anastasiia Gusach,
Alexey Mishin,
Élie Besserer-Offroy,
Jean-Michel Longpré,
Valentin Borshchevskiy,
Vadim Cherezov,
Philippe Sarret,
Vsevolod Katritch
Affiliations
Arman A. Sadybekov
Michelson Center for Convergent Biosciences, Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA
Rebecca L. Brouillette
Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
Egor Marin
Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
Anastasiia V. Sadybekov
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA
Aleksandra Luginina
Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
Anastasiia Gusach
Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
Alexey Mishin
Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
Élie Besserer-Offroy
Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
Jean-Michel Longpré
Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
Valentin Borshchevskiy
Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
Vadim Cherezov
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA
Philippe Sarret
Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
Vsevolod Katritch
Michelson Center for Convergent Biosciences, Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA
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.
