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

doi:10.1021/jm300146f

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Discovery of Novel Small Molecule Inhibitors of Dengue Viral NS2B-NS3 Protease Using Virtual Screening and Scaffold Hopping
	Deng, Jing 3; Li, Ning 4; Liu, Hongchuan 4; Zuo, Zhili 2; Liew, Oi Wah 1; Xu, Weijun 2; Chen, Gang 2; Tong, Xiankun4 ; Tang, Wei4 ; Zhu, Jin 3
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2012-07-26
卷号	55 期号:14 页码:6278-6293
ISSN号	0022-2623
DOI	10.1021/jm300146f
文献子类	Article
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.
资助项目	International S&T Cooperation Project[2010DFB73280] ; National Natural Science Foundation of China[21002028] ; National S&T Major Project, China[2011ZX09102-005-02] ; 111 Project[B07023] ; Shanghai Committee of Science and Technology[11DZ2260600] ; Hundred Talent Program of the Chinese Academy of Sciences[00000000] ; Fundamental Research Funds for the Central Universities[00000000]
WOS关键词	VIRUS NS3 PROTEASE ; SERINE-PROTEASE ; PEPTIDE INHIBITORS ; IN-VITRO ; DESIGN ; TYPE-2 ; FLAVIVIRUSES ; PESTIVIRUSES ; EXPRESSION ; STRATEGIES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000306764600003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278011]
专题	药理学第一研究室药物发现与设计中心药理学第三研究室
通讯作者	Tang, Wei
作者单位	1.Natl Univ Singapore, Yong Loo Lin Sch Med, Cardiovasc Res Inst, Singapore 117599, Singapore 2.Singapore Polytech, Ctr Biomed & Life Sci, Singapore 139651, Singapore; 3.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Deng, Jing,Li, Ning,Liu, Hongchuan,et al. Discovery of Novel Small Molecule Inhibitors of Dengue Viral NS2B-NS3 Protease Using Virtual Screening and Scaffold Hopping[J]. JOURNAL OF MEDICINAL CHEMISTRY,2012,55(14):6278-6293.
APA	Deng, Jing.,Li, Ning.,Liu, Hongchuan.,Zuo, Zhili.,Liew, Oi Wah.,...&Zhu, Weiliang.(2012).Discovery of Novel Small Molecule Inhibitors of Dengue Viral NS2B-NS3 Protease Using Virtual Screening and Scaffold Hopping.JOURNAL OF MEDICINAL CHEMISTRY,55(14),6278-6293.
MLA	Deng, Jing,et al."Discovery of Novel Small Molecule Inhibitors of Dengue Viral NS2B-NS3 Protease Using Virtual Screening and Scaffold Hopping".JOURNAL OF MEDICINAL CHEMISTRY 55.14(2012):6278-6293.