Optimization of Adenosine
5′-Carboxamide Derivatives
as Adenosine Receptor Agonists Using Structure-Based Ligand Design
and Fragment Screening
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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<sub>2A</sub> 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<sub>1</sub>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