title: Optimization of adenosine 5'-carboxamide derivatives as adenosine receptor agonists using structure-based ligand design and fragment screening.
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.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.forename: Khai
authors.initials: K
authors.lastname: Phan
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Gakh
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.forename: Francesca
authors.initials: F
authors.lastname: Deflorian
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D011485:Protein Binding; D058906:Purinergic P1 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D058906:Purinergic P1 Receptor Agonists; D043705:Receptor, Adenosine A2A; C018196:adenosine 5'-carboxamide; D000241:Adenosine