title: A steric and electrostatic comparison of three models for the agonist/antagonist binding site on the adenosine A1 receptor.
abstract: Several models have been described in the literature to explain the similarity of interaction of adenosine receptor agonists and antagonists with the binding site of the receptor. Besides the superposition of the nitrogen atoms of adenosine and xanthine (the "standard" model), two other models have been described: one in which xanthine is rotated around its "horizontal" axis before superposition ("flipped") and one in which the adenosine N6-region and the xanthine C8-region are superimposed ("N6-C8"). In this study we compared the steric and electrostatic properties of these models. The flipped model tends to show higher percentages of overlap for the positive electrostatic potentials and the N6-C8 model yielded predominantly a slightly higher overlap for the negative electrostatic potentials, although these differences were rather small. Since the N6-region in adenosine and the C8-region in xanthine are coinciding in this model, the N6-C8 model yielded a much larger overlap in van der Waals volume than the other two models. The N6-C8 model seems therefore to be the more probable model, also because the interactive groups point in the same direction for both adenosine and xanthine analogues. We determined the geometries of both the adenosine N6-substituents and the xanthine 8-substituents in earlier studies. The N6-C8 model causes a coincidence of these separately determined conformations.
authors.affiliation: Center for Bio-Pharmaceutical Sciences, Division of Medicinal Chemistry, Leiden, The Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: van der Wenden
authors.forename: A P
authors.initials: AP
authors.lastname: Ijzerman
authors.forename: W
authors.initials: W
authors.lastname: Soudijn
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004563:Electrochemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D058914:Purinergic Antagonists; D011983:Receptors, Purinergic / Q000378:metabolism*; D012044:Regression Analysis; D013329:Structure-Activity Relationship; D019820:Xanthine; D014970:Xanthines / Q000737:chemistry* / Q000378:metabolism
chemical_list: D058914:Purinergic Antagonists; D011983:Receptors, Purinergic; D014970:Xanthines; D019820:Xanthine; D000241:Adenosine