| 摘要: | 組蛋白去乙醯酶 (histone deacetylases, HDACs) 為調控表觀遺傳調控之一種酵素群，組蛋白去乙醯酶可由其同源性、催化活性、組織分佈分成四類，其中Class IIa型組蛋白去乙醯酶被認為在許多疾病中扮演重要角色，如癌細胞發展、糖尿病腎病變、發炎性疾病、神經退化性疾病等疾病中扮演重要角色，因此被認為是重要藥物標靶。大多數的組蛋白去乙醯酶抑制劑都包含異羥肟酸的結構，用來熬合組蛋白去乙醯酶活性部位的鋅離子，但是異羥肟酸具有不佳的藥物動力學表現以及較強的細胞毒性等問題，再者，以異羥肟酸為主的組蛋白去乙醯酶抑制劑對於組蛋白去乙醯酶的四個分類沒有選擇性，因此延伸出許多副作用。本研究主要以分子嵌合模擬方法，透過電腦虛擬篩選(Virtual screening)分析發展出6個新的非異羥肟酸組蛋白去乙醯酶抑制劑，對Class IIa型組蛋白去乙醯酶展現出抑制活性(IC50 <10 μM)，而對Hela nuclear extract (包含HDAC1, HDAC2, HDAC3)組蛋白去乙醯酶則沒有顯著抑制活性，可以顯示出這些抑制劑對Class IIa型組蛋白去乙醯酶具有選擇性，我們相信本研究對研發低副作用之非異羥肟酸組蛋白去乙醯酶抑制劑非常有發展潛力。
Histone deacetylases (HDACs) are a family of enzymes that regulate epigenetic process by removing acetyl groups from histone. HDACs are divided into 4 classes based on their sequence homology, catalytic site and tissue distribution. Class IIa HDACs has been considered to play an important role in various diseases, such as diabetic nephropathy, cancers, Neurodegeneration and inflammatory disease, thus becoming vital drug targets. Most of HDAC inhibitors contain a common moiety, hydroxamate, which chelates the Zinc ion in binding site. However, such inhibitors have two major problems, namely poor pharmacokinetics and severe toxicity. In addition, hydroxamate-based inhibitors often have no selectivity for the 4 classes of HDACs, leading to side effects. Here, we identified 6 functional groups that is able to coordinate the Zinc ion from protein-ligand complexes in the Protein Data Bank. Based on these functional groups, 6 new non-hydroxamate inhibitors were identified using structure-based virtual screening. The new inhibitors exhibited enzyme-inhibitory activities (IC50 <10 μM) against class IIA HDACs. In comparison, they showed weak inhibitory activities against Hela nuclear HDAC that contains class I HDACs, suggesting their selectivity for class IIA HDACs. We believe that these inhibitors provide promising starting points to develop non-hydroxamate HADC drugs with low side effects. |
