title: Predicted ligands for the human urotensin-II G protein-coupled receptor with some experimental validation.
abstract: Human Urotensin-II (U-II) is the most potent mammalian vasoconstrictor known.1 Thus, a U-II antagonist would be of therapeutic value in a number of cardiovascular disorders.2 Here, we describe our work on the prediction of the structure of the human U-II receptor (hUT2 R) using GEnSeMBLE (GPCR Ensemble of Structures in Membrane BiLayer Environment) complete sampling Monte Carlo method. With the validation of our predicted structures, we designed a series of new potential antagonists predicted to bind more strongly than known ligands. Next, we carried out R-group screening to suggest a new ligand predicted to bind with 7 kcal mol(-1) better energy than 1-{2-[4-(2-bromobenzyl)-4-hydroxypiperidin-1-yl]ethyl}-3-(thieno[3,2-b]pyridin-7-yl)urea, the designed antagonist predicted to have the highest affinity for the receptor. Some of these predictions were tested experimentally, validating the computational results. Using the pharmacophore generated from the predicted structure for hUT2 R bound to ACT-058362, we carried out virtual screening based on this binding site. The most potent hit compounds identified contained 2-(phenoxymethyl)-1,3,4-thiadiazole core, with the best derivative exhibiting an IC50 value of 0.581 μM against hUT2 R when tested in vitro. Our efforts identified a new scaffold as a potential new lead structure for the development of novel hUT2 R antagonists, and the computational methods used could find more general applicability to other GPCRs.
authors.affiliation: Materials & Process Simulation Center, California Institute of Technology, Beckman Institute (BI);Code (139-74), 1200 E. California Blvd., Pasadena, CA 91125 (USA).
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Kim
authors.forename: William A
authors.initials: WA
authors.lastname: Goddard
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
authors.forename: Chae Jo
authors.initials: CJ
authors.lastname: Lim
authors.forename: Bartosz
authors.initials: B
authors.lastname: Trzaskowski
mesh_terms: D000818:Animals; D001665:Binding Sites; D030562:Databases, Protein; D006801:Humans; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D009010:Monte Carlo Method; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; D014508:Urea; C493249:1-(2-(4-benzyl-4-hydroxypiperidin-1-yl)ethyl)-3-(2-methylquinolin-4-yl)urea
keywords: GPCRs; R-group screening; computational chemistry; docking; urotensin II; virtual screening