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

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• 作者：Elisa M. Nurminen ; Marjo Pihlavisto ; La虂szlo虂 La虂za虂r ; Ulla Pentika虉inen ; Ferenc Fu虉lo虉p ; Olli T. Pentika虉inen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 14, 2011
• 年：2011
• 卷：54
• 期：7
• 页码：2143-2154
• 全文大小：1198K
• 年卷期：v.54,no.7(April 14, 2011)
• ISSN：1520-4804

文摘

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鈥檚 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.