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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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journal contribution
posted on 09.09.2010, 00:00 by Elisa M. Nurminen, Marjo Pihlavisto, László Lázár, Zsolt Szakonyi, Ulla Pentikäinen, Ferenc Fülöp, Olli T. Pentikäinen
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 (q2LOO: 0.636; r2: 0.828) and MAOs (q2LOO: 0.749, r2: 0.840) were built and employed in the development of selective VAP-1 inhibitors.