通过基于机制的药物设计鉴定一种有效的非异羟肟酸类组蛋白脱乙酰酶抑制剂。
Identification of a potent non-hydroxamate histone deacetylase inhibitor by mechanism-based drug design.
作者信息
Suzuki Takayoshi, Matsuura Azusa, Kouketsu Akiyasu, Nakagawa Hidehiko, Miyata Naoki
机构信息
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
出版信息
Bioorg Med Chem Lett. 2005 Jan 17;15(2):331-5. doi: 10.1016/j.bmcl.2004.10.074.
In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, we synthesized several suberoylanilide hydroxamic acid (SAHA)-based compounds designed on the basis of the catalytic mechanism of HDACs. Among these compounds, 5b was found to be as potent as SAHA. Kinetic enzyme assays and molecular modeling suggested that the mercaptoacetamide moiety of 5b interacts with the zinc in the active site of HDACs and removes a water molecule from the reactive site of the deacetylation.
为了寻找新型非异羟肟酸类组蛋白去乙酰化酶（HDAC）抑制剂，我们基于HDAC的催化机制合成了几种基于辛二酰苯胺异羟肟酸（SAHA）的化合物。在这些化合物中，发现5b与SAHA具有同等效力。动力学酶分析和分子模拟表明，5b的巯基乙酰胺部分与HDAC活性位点中的锌相互作用，并从去乙酰化反应位点去除一个水分子。
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