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

被引：23

作者：

Nurminen, Elisa M. ^{[1
,2
]}

Pihlavisto, Marjo ^{[3
]}

Lazar, Laszlo ^{[4
]}

Pentikainen, Ulla ^{[1
,2
]}

Fueloep, Ferenc ^{[4
]}

Pentikainen, Olli T. ^{[1
,2
]}

机构：

[1] Univ Jyvaskyla, Dept Biol, FI-40014 Jyvaskyla, Finland

[2] Univ Jyvaskyla, Environm Sci & Nanosci Ctr, FI-40014 Jyvaskyla, Finland

[3] BioTie Therapies Corp, FI-20520 Turku, Finland

[4] Univ Szeged, Inst Pharmaceut Chem, H-6720 Szeged, Hungary

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 07期

基金：

芬兰科学院;

关键词：

SENSITIVE AMINE OXIDASE; SMOOTH-MUSCLE-CELLS; MECHANICAL CALCULATIONS; ALZHEIMERS-DISEASE; GLUCOSE-METABOLISM; DIABETES-MELLITUS; ESCHERICHIA-COLI; CIRCULATING FORM; SSAO ACTIVITY; SERUM-LEVELS;

D O I：

10.1021/jm200059p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：2143 / 2154

页数：12