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J Med Chem. 2012 May 10;55(9):4297-308. doi: 10.1021/jm300095s. Epub 2012 Apr 30.

Optimization of adenosine 5'-carboxamide derivatives as adenosine receptor agonists using structure-based ligand design and fragment screening.

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1
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

Abstract

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 A(2A) 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 A(1)AR 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.

PMID:
22486652
PMCID:
PMC3479662
DOI:
10.1021/jm300095s
[Indexed for MEDLINE]
Free PMC Article
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