title: Comparative analysis of putative agonist-binding modes in the human A1 adenosine receptor.
abstract: A recent study reported a model of the human A(1) adenosine receptor and its agonist binding site, proposing two putative binding modes in the same binding site for the natural agonist, adenosine. The present work investigates the flexibility of this binding site by exhaustive exploration with the natural agonist and with three other adenosine derivatives: N6-cyclopentyladenosine (CPA), 2-chloro-N6-cyclopentyladenosine (CCPA), and 5'-N-ethylcarboxamidoadenosine (NECA). Our aim was to find a common binding mode for agonists that would explain the role in the binding process of the different substitutions allowed at the 2, N6, and 5' positions of adenosine. This problem was addressed through docking simulations, molecular dynamics studies, and estimations of the ligand-binding free energy with both the AUTODOCK scoring function and the linear interaction energy (LIE) approach. The results point to a single receptor-binding position that explains the effects of the different chemical modifications on the adenosine derivatives considered here.
authors.affiliation: Research Group on Biomedical Informatics (GRIB), Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, Carrer Dr. Aiguader 80, 08003 Barcelona, Spain.
authors.forename: Hugo
authors.initials: H
authors.lastname: Gutiérrez-de-Terán
authors.forename: Manuel
authors.initials: M
authors.lastname: Pastor
authors.forename: Nuria B
authors.initials: NB
authors.lastname: Centeno
authors.forename: Johan
authors.initials: J
authors.lastname: Aqvist
authors.forename: Ferran
authors.initials: F
authors.lastname: Sanz
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058907:Adenosine A1 Receptor Agonists; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D001665:Binding Sites; D006801:Humans; D008433:Mathematics; D008958:Models, Molecular; D043682:Receptor, Adenosine A1 / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D058907:Adenosine A1 Receptor Agonists; D043682:Receptor, Adenosine A1; D019830:Adenosine-5'-(N-ethylcarboxamide); C058394:2-chloro-N(6)cyclopentyladenosine; C048599:N(6)-cyclopentyladenosine; D000241:Adenosine