Synthesis, in vitro activity, and three-dimensional quantitative Structure-activity relationship of novel hydrazine inhibitors of human vascular adhesion protein-1

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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 (q2LOO: 0.636; r2: 0.828) and MAOs (q2LOO: 0.749, r2: 0.840) were built and employed in the development of selective VAP-1 inhibitors.

Original languageEnglish
Pages (from-to)6301-6315
Number of pages15
JournalJournal of Medicinal Chemistry
Volume53
Issue number17
DOIs
Publication statusPublished - Sep 9 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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