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J Med Chem. 2010 Sep 9;53(17):6301-15. doi: 10.1021/jm100337z.

Synthesis, in vitro activity, and three-dimensional quantitative structure-activity relationship of novel hydrazine inhibitors of human vascular adhesion protein-1.

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Department of Biological and Environmental Science & Nanoscience Center, PO Box 35, FI-40014 University of Jyvaskyla, Finland.


Vascular adhesion protein-1 (VAP-1) belongs to the semicarbazide-sensitive amine oxidases (SSAOs) that convert amines into aldehydes. SSAOs are distinct from the mammalian monoamine oxidases (MAOs), but their substrate specificities are partly overlapping. VAP-1 has been proposed as a target for anti-inflammatory drug therapy because of its role in leukocyte adhesion to endothelium. Here, we describe the synthesis and in vitro activities of novel series of VAP-1 selective inhibitors. In addition, the molecular dynamics simulations performed for VAP-1 reveal that the movements of Met211, Ser496, and especially Leu469 can enlarge the ligand-binding pocket, allowing larger ligands than those seen in the crystal structures to bind. Combining the data from molecular dynamics simulations, docking, and in vitro measurements, the three-dimensional quantitative structure-activity relationship (3D QSAR) models for VAP-1 (q(2)(LOO): 0.636; r(2): 0.828) and MAOs (q(2)(LOO): 0.749, r(2): 0.840) were built and employed in the development of selective VAP-1 inhibitors.

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