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Predicted Ligands for the Human Urotensin-II G Protein-Coupled Receptor with Some Experimental Validation

Kim, Soo-Kyung and Goddard, William A., III and Yi, Kyu Yang and Lee, Byung Ho and Lim, Chae Jo and Trzaskowski, Bartosz (2014) Predicted Ligands for the Human Urotensin-II G Protein-Coupled Receptor with Some Experimental Validation. ChemMedChem, 9 (8). pp. 1732-1743. ISSN 1860-7179. https://resolver.caltech.edu/CaltechAUTHORS:20140707-153310369

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Abstract

Human Urotensin-II (U-II) is the most potent mammalian vasoconstrictor known. Thus, a U-II antagonist would be of therapeutic value in a number of cardiovascular disorders. Here, we describe our work on the prediction of the structure of the human U-II receptor (hUT2R) 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 hUT2R 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 hUT2R when tested in vitro. Our efforts identified a new scaffold as a potential new lead structure for the development of novel hUT2R antagonists, and the computational methods used could find more general applicability to other GPCRs.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1002/cmdc.201402087DOIArticle
http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201402087/abstractPublisherArticle
http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201402087/suppinfoPublisherSupporting Information
ORCID:
AuthorORCID
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Received March 26, 2014. Funding for this project was provided by the Korea Research Institute of Chemical Technology (South Korea).
Funders:
Funding AgencyGrant Number
Korea Research Institute of Chemical TechnologyUNSPECIFIED
Issue or Number:8
Record Number:CaltechAUTHORS:20140707-153310369
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140707-153310369
Official Citation:Kim, S.-K., Goddard, W. A., Yi, K. Y., Lee, B. H., Lim, C. J. and Trzaskowski, B. (2014), Predicted Ligands for the Human Urotensin-II G Protein-Coupled Receptor with Some Experimental Validation. ChemMedChem, 9: 1732–1743. doi: 10.1002/cmdc.201402087
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:46907
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:07 Jul 2014 22:59
Last Modified:26 Nov 2019 11:15

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