Paper Citing NAMD - Abstract
Nurminen, Elisa M.; Pihlavisto, Marjo; Lazar, Laszlo; Szakonyi, Zsolt; Pentikainen, Ulla; Fulop, Ferenc; Pentikainen, Olli T.
Synthesis, in Vitro Activity, and Three-Dimensional Quantitative Structure-Activity Relationship of Novel Hydrazine Inhibitors of Human Vascular Adhesion Protein-1
JOURNAL OF MEDICINAL CHEMISTRY, 53:6301-6315, SEP 9 2010
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(LOO)(2): 0.636; r(2:) 0.828) and MAOs (q(LOO)(2): 0.749, r(2): 0.840) were built and employed in the development of selective VAP-1 inhibitors.
