Novel hydrazine molecules as tools to understand the flexibility of vascular adhesion protein-1 ligand-binding site: Toward more selective inhibitors

Elisa M. Nurminen, Marjo Pihlavisto, László Lázár, Ulla Pentikäinen, Ferenc Fülöp, Olli T. Pentikäinen

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18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2143-2154
Number of pages12
JournalJournal of Medicinal Chemistry
Volume54
Issue number7
DOIs
Publication statusPublished - Apr 14 2011

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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