Department of Biological and Environmental Science and Nanoscience Center, University of Jyväskylä, P.O. Box 35, FI-40014 Jyväskylä, Finland.
J Med Chem. 2011 Apr 14;54(7):2143-54. doi: 10.1021/jm200059p. Epub 2011 Mar 15.
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.
血管黏附蛋白-1（VAP-1）属于胺氧化酶家族。它在白细胞迁移和胺化合物代谢中发挥作用。VAP-1 与各种疾病有关，如阿尔茨海默病、银屑病、抑郁症、糖尿病和肥胖症。因此，VAP-1 的选择性抑制剂可能被用于治疗这些疾病。在这项研究中，合成了 8 种新型 VAP-1 腙衍生物，并在体外测定了它们对 VAP-1 和单胺氧化酶（MAO）的抑制能力。与这些新分子的 VAP-1 的 MD 模拟表明，VAP-1 的配体结合口袋是灵活的，能够容纳比以前认为的更大的配体。VAP-1 配体的尺寸增加，加上腙部分的仲氮原子的甲基化，提高了 VAP-1 对 MAO 的选择性。
