title: Revisiting a receptor-based pharmacophore hypothesis for human A(2A) adenosine receptor antagonists.
abstract: The application of both structure- and ligand-based design approaches represents to date one of the most useful strategies in the discovery of new drug candidates. In the present paper, we investigated how the application of docking-driven conformational analysis can improve the predictive ability of 3D-QSAR statistical models. With the use of the crystallographic structure in complex with the high affinity antagonist ZM 241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol), we revisited a general pharmacophore hypothesis for the human A(2A) adenosine receptor of a set of 751 known antagonists, by applying an integrated ligand- and structure-based approach. Our novel pharmacophore hypothesis has been validated by using an external test set of 29 newly synthesized human adenosine receptor antagonists.
authors.affiliation: Molecular Modeling Section-MMS, Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, Padova, Italy.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Bacilieri
authors.forename: Antonella
authors.initials: A
authors.lastname: Ciancetta
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.forename: Stephanie
authors.initials: S
authors.lastname: Federico
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Barbara
authors.initials: B
authors.lastname: Cacciari
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Karl Norbert
authors.initials: KN
authors.lastname: Klotz
authors.forename: Giampiero
authors.initials: G
authors.lastname: Spalluto
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism*; D055672:Static Electricity; D014227:Triazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385