Discovery of Inhibitors To Block Interactions of HIV-1 Integrase with Human LEDGF/p75 via Structure-Based Virtual Screening and Bioassays

doi:10.1021/jm301226a

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 上海中药现代化研究中心

	Discovery of Inhibitors To Block Interactions of HIV-1 Integrase with Human LEDGF/p75 via Structure-Based Virtual Screening and Bioassays
	Hu, Guoping 1; Li, Xi 1; Zhang, Xuan 3; Li, Yaozong 1; Ma, Lei 1; Yang, Liu-Meng 3; Liu, Guixia 1; Li, Weihua 1; Huang, Jin 1; Shen, Xu2
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2012-11-22
卷号	55 期号:22 页码:10108-10117
ISSN号	0022-2623
DOI	10.1021/jm301226a
文献子类	Article
英文摘要	This study aims to identify inhibitors that bind at the interface of HIV-1 integrase (IN) and human LEDGF/p75, which represents a novel target for anti-HIV therapy. To date, only a few such inhibitors have been reported. Here structure-based virtual screening was performed to search for the inhibitors from an in-house library of natural products and their derivatives. Among the 38 compounds selected by our strategy, 18 hits were discovered. The two most potent inhibitors showed IC50 values at 0.32 and 0.26 mu M, respectively. Three compounds were subsequently selected for anti-HIV assays, among which (E)-3-(2-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one (NPD170) showed the highest antiviral activity (EC50 = 1.81 mu M). The antiviral mechanism of these compounds was further explored, and the results validated that the compounds interrupted the binding of transfected IN to endogenous LEDGF/p75. These findings could be helpful for anti-HIV drug discovery.
资助项目	Program for New Century Excellent Talents in University[NCET-08-0774] ; Fundamental Research Funds for the Central Universities[WY1113007] ; Shanghai Committee of Science and Technology[11DZ2260600] ; National Natural Science Foundation of China[30925040] ; National Natural Science Foundation of China[81102483] ; Key Scientific and Technological Program of China[2012ZX10001-006] ; Key Scientific and Technological Program of China[2012ZX09103-101-022]
WOS关键词	SMALL-MOLECULE INHIBITORS ; PROTEIN-PROTEIN INTERACTIONS ; CELLULAR COFACTORS ; DNA INTEGRATION ; DRUG DISCOVERY ; BINDING-SITE ; IN-VITRO ; REPLICATION ; MULTIMERIZATION ; INTERFACES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000311461500057
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277874]
专题	上海中药现代化研究中心药理学第三研究室
通讯作者	Huang, Jin
作者单位	1.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Res Ctr Modernizat Tradit Chinese Med, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Kunming Inst Zool, Chinese Acad Sci & Yunnan, Key Lab Anim Models & Human Dis Mech, Kunming 650223, Peoples R China;
推荐引用方式 GB/T 7714	Hu, Guoping,Li, Xi,Zhang, Xuan,et al. Discovery of Inhibitors To Block Interactions of HIV-1 Integrase with Human LEDGF/p75 via Structure-Based Virtual Screening and Bioassays[J]. JOURNAL OF MEDICINAL CHEMISTRY,2012,55(22):10108-10117.
APA	Hu, Guoping.,Li, Xi.,Zhang, Xuan.,Li, Yaozong.,Ma, Lei.,...&Tang, Yun.(2012).Discovery of Inhibitors To Block Interactions of HIV-1 Integrase with Human LEDGF/p75 via Structure-Based Virtual Screening and Bioassays.JOURNAL OF MEDICINAL CHEMISTRY,55(22),10108-10117.
MLA	Hu, Guoping,et al."Discovery of Inhibitors To Block Interactions of HIV-1 Integrase with Human LEDGF/p75 via Structure-Based Virtual Screening and Bioassays".JOURNAL OF MEDICINAL CHEMISTRY 55.22(2012):10108-10117.