title: Novel hydrazine molecules as tools to understand the flexibility of vascular adhesion protein-1 ligand-binding site: toward more selective inhibitors.
abstract: Vascular adhesion protein-1 (VAP-1) belongs to a family of amine oxidases. It plays a role in leukocyte trafficking and in amine compound metabolism. VAP-1 is linked to various diseases, such as Alzheimer's disease, psoriasis, depression, diabetes, and obesity. Accordingly, selective inhibitors of VAP-1 could potentially be used to treat those diseases. In this study, eight novel VAP-1 hydrazine derivatives were synthesized and their VAP-1 and monoamine oxidase (MAO) inhibition ability was determined in vitro. MD simulations of VAP-1 with these new molecules reveal that the VAP-1 ligand-binding pocket is flexible and capable of fitting substantially larger ligands than was previously believed. The increase in the size of the VAP-1 ligands, together with the methylation of the secondary nitrogen atom of the hydrazine moiety, improves the VAP-1 selectivity over MAO.
authors.affiliation: Department of Biological and Environmental Science and Nanoscience Center, University of Jyväskylä, P.O. Box 35, FI-40014 Jyväskylä, 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: 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 / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D015815:Cell Adhesion Molecules; D006834:Hydrazines; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; C029424:hydrazine; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); D008995:Monoamine Oxidase