title: Evaluation of molecular modeling of agonist binding in light of the crystallographic structure of an agonist-bound A₂A adenosine receptor.
abstract: Molecular modeling of agonist binding to the human A(2A) 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 A(2A)AR 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 A(2A)AR 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.
authors: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 8A, Room B1A-19, Bethesda, Maryland 20892-0810, United States.
authors: Francesca
authors: F
authors: Deflorian
authors: T Santhosh
authors: TS
authors: Kumar
authors: Khai
authors: K
authors: Phan
authors: Zhan-Guo
authors: ZG
authors: Gao
authors: Fei
authors: F
authors: Xu
authors: Huixian
authors: H
authors: Wu
authors: Vsevolod
authors: V
authors: Katritch
authors: Raymond C
authors: RC
authors: Stevens
authors: Kenneth A
authors: KA
authors: Jacobson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009705:Nucleosides / Q000737:chemistry*; D010627:Phenethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D058908:Adenosine A2 Receptor Agonists; D000596:Amino Acids; D008024:Ligands; D009705:Nucleosides; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine