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RESEARCH PRODUCT

Novel Hydrazine Molecules as Tools To Understand the Flexibility of Vascular Adhesion Protein-1 Ligand-Binding Site: Toward More Selective Inhibitors

Ulla PentikäinenElisa M. NurminenFerenc FülöpLászló LázárMarjo PihlavistoOlli T. Pentikäinen

subject

Monoamine Oxidase InhibitorsProtein ConformationMonoamine oxidaseCHO CellsMolecular Dynamics SimulationLigandsSubstrate SpecificityStructure-Activity RelationshipCricetulusCricetinaeDrug DiscoveryAnimalsHumansMoietyHydrazine (antidepressant)Monoamine OxidaseBinding SitesChemistryMethylationAdhesionbacterial infections and mycosesIn vitroRatsrespiratory tract diseasesHydrazinesBiochemistryMolecular MedicineAmine gas treatingAmine Oxidase (Copper-Containing)SelectivityCell Adhesion Molecules

description

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.

yearjournalcountryeditionlanguage
2011-03-15Journal of Medicinal Chemistry
https://doi.org/10.1021/jm200059p