jm201461q_si_003.pdb (367.76 kB)
Evaluation of Molecular Modeling of Agonist Binding in Light of the Crystallographic Structure of an Agonist-Bound A2A Adenosine Receptor
dataset
posted on 2012-01-12, 00:00 authored by Francesca Deflorian, T. Santhosh Kumar, Khai Phan, Zhan-Guo Gao, Fei Xu, Huixian Wu, Vsevolod Katritch, Raymond
C. Stevens, Kenneth A. JacobsonMolecular modeling of agonist binding to the human A2A adenosine receptor (AR) was assessed and extended in light
of crystallographic
structures. Heterocyclic adenine nitrogens of cocrystallized agonist
overlaid corresponding positions of the heterocyclic base of a bound
triazolotriazine antagonist, and ribose moiety was coordinated in
a hydrophilic region, as previously predicted based on modeling using
the inactive receptor. Automatic agonist docking of 20 known potent
nucleoside agonists to agonist-bound A2AAR crystallographic
structures predicted new stabilizing protein interactions to provide
a structural basis for previous empirical structure activity relationships
consistent with previous mutagenesis results. We predicted binding
of novel C2 terminal amino acid conjugates of A2AAR agonist
CGS21680 and used these models to interpret effects on binding affinity
of newly synthesized agonists. d-Amino acid conjugates were
generally more potent than l-stereoisomers and free terminal
carboxylates more potent than corresponding methyl esters. Amino acid
moieties were coordinated close to extracellular loops 2 and 3. Thus,
molecular modeling is useful in probing ligand recognition and rational
design of GPCR-targeting compounds with specific pharmacological profiles.
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terminal carboxylatesprotein interactionstriazolotriazine antagonistAgonist BindingHeterocyclic adenine nitrogensligand recognitionAmino acid moietiesribose moietymutagenesis resultsnovel C 2 terminalMolecular Modelingextracellular loops 2structure activity relationshipsagonist bindingAutomatic agonist dockingheterocyclic base2AAR agonist CGS 21680binding affinity2A Adenosine ReceptorMolecular modelingacid conjugatesmethyl estersCrystallographic Structure2A adenosine receptornucleoside agonistscocrystallized agonist
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