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Crystal structure of human vascular adhesion protein-1 in complex with pyridazinone inhibitorsCrystal structure of human vascular adhesion protein-1 in complex with pyridazinone inhibitors
Structural highlights
FunctionAOC3_HUMAN Cell adhesion protein that participates in lymphocyte recirculation by mediating the binding of lymphocytes to peripheral lymph node vascular endothelial cells in an L-selectin-independent fashion. Has a monoamine oxidase activity. May play a role in adipogenesis.[1] [2] [3] Publication Abstract from PubMedVascular 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. Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target-New Inhibition Mode.,Bligt-Linden E, Pihlavisto M, Szatmari I, Otwinowski Z, Smith DJ, Lazar L, Fulop F, Salminen TA J Med Chem. 2013 Dec 13. PMID:24304424[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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