title: Identification of novel adenosine A(2A) receptor antagonists by virtual screening.
abstract: Virtual screening was performed against experimentally enabled homology models of the adenosine A(2A) receptor, identifying a diverse range of ligand efficient antagonists (hit rate 9%). By use of ligand docking and Biophysical Mapping (BPM), hits 1 and 5 were optimized to potent and selective lead molecules (11-13 from 5, pK(I) = 7.5-8.5, 13- to >100-fold selective versus adenosine A(1); 14-16 from 1, pK(I) = 7.9-9.0, 19- to 59-fold selective).
authors.affiliation: Heptares Therapeutics Limited, BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, UK. chris.langmead@heptares.com
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Langmead
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Andrews
authors.forename: Miles
authors.initials: M
authors.lastname: Congreve
authors.forename: James C
authors.initials: JC
authors.lastname: Errey
authors.forename: Edward
authors.initials: E
authors.lastname: Hurrell
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Marshall
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Mason
authors.forename: Christine M
authors.initials: CM
authors.lastname: Richardson
authors.forename: Nathan
authors.initials: N
authors.lastname: Robertson
authors.forename: Andrei
authors.initials: A
authors.lastname: Zhukov
authors.forename: Malcolm
authors.initials: M
authors.lastname: Weir
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D016208:Databases, Factual; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014422:Turkeys
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D002867:Chromones; D010879:Piperazines; D043705:Receptor, Adenosine A2A; D014227:Triazines