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Optimization of Adenosine 5′-Carboxamide Derivatives as Adenosine Receptor Agonists Using Structure-Based Ligand Design and Fragment Screening

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† Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States
‡ Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
§ University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, 9500 Gilman Drive, La Jolla, California 92093, United States
*For V.K.: phone, 858-784-7723; E-mail, [email protected]. For K.A.J.: phone, 301-496-9024; E-mail, [email protected]
Cite this: J. Med. Chem. 2012, 55, 9, 4297–4308
Publication Date (Web):April 9, 2012
https://doi.org/10.1021/jm300095s
Copyright © 2012 American Chemical Society
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    Abstract

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    Structures of G protein-coupled receptors (GPCRs) have a proven utility in the discovery of new antagonists and inverse agonists modulating signaling of this important family of clinical targets. Applicability of active-state GPCR structures to virtual screening and rational optimization of agonists, however, remains to be assessed. In this study of adenosine 5′ derivatives, we evaluated the performance of an agonist-bound A2A adenosine receptor (AR) structure in retrieval of known agonists and then employed the structure to screen for new fragments optimally fitting the corresponding subpocket. Biochemical and functional assays demonstrate high affinity of new derivatives that include polar heterocycles. The binding models also explain modest selectivity gain for some substituents toward the closely related A1AR subtype and the modified agonist efficacy of some of these ligands. The study suggests further applicability of in silico fragment screening to rational lead optimization in GPCRs.

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    Known A2AAR agonists used in the initial docking model assessments. 3D binding models and scores for all ligands in Table 1. Synthetic procedures for the nucleoside derivatives and their characterization. This material is available free of charge via the Internet at http://pubs.acs.org.

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