title: Novel pyridazinone inhibitors for vascular adhesion protein-1 (VAP-1): old target-new inhibition mode.
abstract: Vascular adhesion protein-1 (VAP-1) is a primary amine oxidase and a drug target for inflammatory and vascular diseases. Despite extensive attempts to develop potent, specific, and reversible inhibitors of its enzyme activity, the task has proven challenging. Here we report the synthesis, inhibitory activity, and molecular binding mode of novel pyridazinone inhibitors, which show specificity for VAP-1 over monoamine and diamine oxidases. The crystal structures of three inhibitor-VAP-1 complexes show that these compounds bind reversibly into a unique binding site in the active site channel. Although they are good inhibitors of human VAP-1, they do not inhibit rodent VAP-1 well. To investigate this further, we used homology modeling and structural comparison to identify amino acid differences, which explain the species-specific binding properties. Our results prove the potency and specificity of these new inhibitors, and the detailed characterization of their binding mode is of importance for further development of VAP-1 inhibitors.
authors.affiliation: Structural Bioinformatics Laboratory, Department of Biosciences, Åbo Akademi University , FI-20520 Turku, Finland.
authors.forename: Eva
authors.initials: E
authors.lastname: Bligt-Lindén
authors.forename: Marjo
authors.initials: M
authors.lastname: Pihlavisto
authors.forename: István
authors.initials: I
authors.lastname: Szatmári
authors.forename: Zbyszek
authors.initials: Z
authors.lastname: Otwinowski
authors.forename: David J
authors.initials: DJ
authors.lastname: Smith
authors.forename: László
authors.initials: L
authors.lastname: Lázár
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
authors.forename: Tiina A
authors.initials: TA
authors.lastname: Salminen
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D011724:Pyridazines; D011994:Recombinant Proteins; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing)