title: Synthesis, in vitro activity, and three-dimensional quantitative structure-activity relationship of novel hydrazine inhibitors of human vascular adhesion protein-1.
abstract: 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.
authors.affiliation: Department of Biological and Environmental Science & Nanoscience Center, PO Box 35, FI-40014 University of Jyvaskyla, Finland.
authors.forename: Elisa M
authors.initials: EM
authors.lastname: Nurminen
authors.forename: Marjo
authors.initials: M
authors.lastname: Pihlavisto
authors.forename: László
authors.initials: L
authors.lastname: Lázár
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szakonyi
authors.forename: Ulla
authors.initials: U
authors.lastname: Pentikäinen
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
authors.forename: Olli T
authors.initials: OT
authors.lastname: Pentikäinen
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D008995:Monoamine Oxidase / Q000737:chemistry; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013237:Stereoisomerism
chemical_list: D015815:Cell Adhesion Molecules; D006834:Hydrazines; D008024:Ligands; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); D008995:Monoamine Oxidase