title: Exploring the molecular basis of selectivity in A1 adenosine receptors agonists: a case study.
abstract: Adenosine is a naturally occurring purine nucleoside that has a wide variety of well-documented regulatory functions and physiological roles. Selective activation of the adenosine A1 receptor has drawn attention in drug discovery for the therapeutic effects on neural and cardiovascular disorders. We have developed a model of the human A1 adenosine receptor using bovine rhodopsin as a template. A flexible docking approach has been subsequently carried out for evaluating the molecular interactions of twenty-one selective A1 agonists with the receptor model. The results of these studies are consistent with mutational and biochemical data. In particular, they highlight a wide hydrogen-bonding network between the nucleoside portion of the ligands and the A1 receptor as well as key amino acids for hydrophobic interactions with the different N6-groups of the agonists. The models presented here provide a detailed molecular map for the selective stimulation of the adenosine A1 receptor subtype and a steady basis for the rational design of new A1 selective ligands.
authors.affiliation: Centre for Computational Science, Department of Chemistry, Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.forename: Giulia
authors.initials: G
authors.lastname: Menozzi
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Francesco
authors.initials: F
authors.lastname: Bondavalli
authors.forename: Angelo
authors.initials: A
authors.lastname: Ranise
authors.forename: Luisa
authors.initials: L
authors.lastname: Mosti
mesh_terms: D000241:Adenosine / Q000737:chemistry; D058907:Adenosine A1 Receptor Agonists; D000595:Amino Acid Sequence; D001483:Base Sequence; D006801:Humans; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D043682:Receptor, Adenosine A1 / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment
chemical_list: D058907:Adenosine A1 Receptor Agonists; D043682:Receptor, Adenosine A1; D000241:Adenosine