文献类型：期刊文献

英文题名：Discovery of Novel Small Molecule Inhibitors of Dengue Viral NS2B-NS3 Protease Using Virtual Screening and Scaffold Hopping

作者：Deng, Jing[2];Li, Ning[1];Liu, Hongchuan[1];Zuo, Zhili[3];Liew, Oi Wah[4];Xu, Weijun[3];Chen, Gang[3];Tong, Xiankun[1];Tang, Wei[1];Zhu, Jin[2];Zuo, Jianping[1];Jiang, Hualiang[1];Yang, Cai-Guang[1];Li, Jian[2];Zhu, Weiliang[1]

机构：[1]Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;[2]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[3]Singapore Polytech, Ctr Biomed & Life Sci, Singapore 139651, Singapore;[4]Natl Univ Singapore, Yong Loo Lin Sch Med, Cardiovasc Res Inst, Singapore 117599, Singapore

年份：2012

卷号：55

期号：14

起止页码：6278

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000306764600003)】；

基金：We thank Dr. C. Klein for the generous gift of NS2B-NS3 expression plasmid. We gratefully acknowledge the financial support from the International S&T Cooperation Project (Grant 2010DFB73280, W.Z.), National Natural Science Foundation of China (Grant 21002028, J.Z.), National S&T Major Project, China (Grant 2011ZX09102-005-02, J.L.), the 111 Project (Grant B07023, J.L.), the Shanghai Committee of Science and Technology (Grant 11DZ2260600, J.L. and Hj.), Hundred Talent Program of the Chinese Academy of Sciences (C.-G.Y.), and the Fundamental Research Funds for the Central Universities (J.L.).

语种：英文

摘要：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.