title: Pharmacophore based receptor modeling: the case of adenosine A3 receptor antagonists. An approach to the optimization of protein models.
abstract: To design and synthesize new potent and selective antagonists of the human A(3) adenosine receptor, pharmacophoric hypotheses were generated with the software Catalyst for a comprehensive set of compounds retrieved from previous literature. Three of these pharmacophores were used to drive the optimization of a molecular model of the receptor built by homology modeling. The alignment of the ligands proposed by Catalyst was then used to manually dock a set of known A(3) antagonists into the binding site, and as a result, the model was able to explain the different binding mode of very active compounds with respect to less active ones and to reproduce, with good accuracy, free energies of binding. The docking highlighted that the nonconserved residue Tyr254 could play an important role for A(3) selectivity, suggesting that a mutagenesis study on this residue could be of interest in this respect. The reliability of the whole approach was successfully tested by rational design and synthesis of new compounds.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tafi
authors.forename: Cesare
authors.initials: C
authors.lastname: Bernardini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
authors.forename: Matteo
authors.initials: M
authors.lastname: Andreini
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ortore
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Francesca
authors.initials: F
authors.lastname: Fruttarolo
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
mesh_terms: D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043684:Receptor, Adenosine A3 / Q000737:chemistry*; D013816:Thermodynamics; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D005663:Furans; D011720:Pyrazoles; D011743:Pyrimidines; D043684:Receptor, Adenosine A3; D014230:Triazoles