Discovery of Novel Small Molecule Inhibitors of Dengue Viral NS2B-NS3 Protease Using Virtual Screening and Scaffold Hopping
Discovery of Novel Small Molecule Inhibitors of Dengue Viral NS2B-NS3 Protease Using Virtual Screening and Scaffold Hopping
复制标题
利用虚拟筛选和支架跳跃发现登革热病毒 NS2B-NS3 蛋白酶的新型小分子抑制剂
DOI：
10.1021/jm300146f
复制
发表时间：
2012-07-26
影响因子：
7.3
通讯作者：
Zhu, Weiliang
中科院分区：
文献类型：
--
作者：
Deng, Jing;Li, Ning;Zhu, Weiliang
通过虚拟筛选，化合物1对NS2B-NS3蛋白酶具有活性（IC50 = 13.12 +/- 1.03 μ M）。合成了化合物1的14个衍生物（22个），从而发现了4个新的具有生物活性的抑制剂。为了扩大抑制剂的化学多样性，在化合物1和22的共同支架的基础上进行了基于小分子的支架跳跃。设计合成了21个含喹啉的新化合物（23,24）。蛋白酶抑制实验表明，12个含有新支架的化合物是NS2B-NS3蛋白酶的抑制剂。基于荧光素酶报告基因复制的实验结果表明，共发现17个新化合物为NS2B-NS3蛋白酶抑制剂，IC50值为7.46 +/- 1.15 ~ 48.59 +/- 3.46 μ M，其中8个化合物属于两种不同的支架，对DENY具有一定的活性。这些新的化学实体可以作为发现抗DENY治疗方法的先导结构。
By virtual screening, compound 1 was found to be active against NS2B-NS3 protease (IC50 = 13.12 +/- 1.03 mu M). Fourteen derivatives (22) of compound 1 were synthesized, leading to the discovery of four new inhibitors with biological activity. In order to expand the chemical diversity of the inhibitors, small-molecule-based scaffold hopping was performed on the basis of the common scaffold of compounds 1 and 22. Twenty-one new compounds (23, 24) containing quinoline (new scaffold) were designed and synthesized. Protease inhibition assays revealed that 12 compounds with the new scaffold are inhibitors of NS2B-NS3 protease. Taken together, 17 new compounds were discovered as NS2B-NS3 protease inhibitors with IC50 values of 7.46 +/- 1.15 to 48.59 +/- 3.46 mu M, and 8 compounds belonging to two different scaffolds are active to some extent against DENY based on luciferase reporter replicon-based assays. These novel chemical entities could serve as lead structures for discovering therapies against DENY.