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Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: A scaffold hopping approach using salicylate and catechol groups

文献类型：期刊论文

作者Fan, Xing2; Zhang, Feng-Hua2; Al-Safi, Rasha I.1; Zeng, Li-Fan2; Shabaik, Yumna1; Debnath, Bikash1; Sanchez, Tino W.1; Odde, Srinivas1; Neamati, Nouri1; Long, Ya-Qiu2
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2011-08-15
卷号19期号:16页码:4935-4952
关键词HIV-1 integrase inhibitors 2,3-Dihydroxybenzamide Strand transfer 3 '-Process LEDGF/p75 Chelation
ISSN号0968-0896
DOI10.1016/j.bmc.2011.06.058
文献子类Article
英文摘要HIV-1 integrase (IN) is a validated therapeutic target for antiviral drug design. However, the emergence of viral strains resistant to clinically studied IN inhibitors demands the discovery of novel inhibitors that are structurally as well mechanistically different. Herein, we describe the design and discovery of novel IN inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75, which is essential for the HIV-1 integration as an IN cofactor. By merging the pharmacophores of salicylate and catechol, the 2,3-dihydroxybenzamide (5a) was identified as a new scaffold to inhibit the strand transfer reaction efficiently. Further structural modifications on the 2,3-dihydroxybenzamide scaffold revealed that the heteroaromatic functionality attached on the carboxamide portion and the piperidin-1-ylsulfonyl substituted at the phenyl ring are beneficial for the activity, resulting in a low micromolar IN inhibitor (5p, IC(50) = 5 mu M) with more than 40-fold selectivity for the strand transfer over the 3'-processing reaction. More significantly, this active scaffold remarkably inhibited the interaction between IN and LEDGF/p75 cofactor. The prototype example, N-(cyclohexylmethyl)-2,3-dihydroxy-5-(piperidin-1-ylsulfonyl) benzamide (5u) inhibited the IN-LEDGF/p75 interaction with an IC(50) value of 8 mu M. Using molecular modeling, the mechanism of action was hypothesized to involve the chelation of the divalent metal ions inside the IN active site. Furthermore, the inhibitor of IN-LEDGF/p75 interaction was properly bound to the LEDGF/p75 binding site on IN. This work provides a new and efficient approach to evolve novel HIV-1 IN inhibitors from rational integration and optimization of previously reported inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.
WOS关键词SMALL-MOLECULE INHIBITORS ; ACCURATE DOCKING ; CHELATION ; EVOLUTION ; DISCOVERY ; INTASOME ; GLIDE ; SITE
资助项目Science and Technology Commission of Shanghai Municipality[08JC1422200] ; National Natural Science Foundation of China[81072527] ; National Science & Technology Major Project 'Key New Drug Creation and Manufacturing Program', China[2009ZX09301-001] ; National Science & Technology Major Project 'Key New Drug Creation and Manufacturing Program', China[2009ZX09103-067] ; NIH/NIAID[R21AI081610]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000293503000027
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/278437]  
专题药物化学研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者Neamati, Nouri
作者单位1.Univ So Calif, Dept Pharmacol & Pharmaceut Sci, Sch Pharm, Los Angeles, CA 90089 USA;
2.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Fan, Xing,Zhang, Feng-Hua,Al-Safi, Rasha I.,et al. Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: A scaffold hopping approach using salicylate and catechol groups[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2011,19(16):4935-4952.
APA Fan, Xing.,Zhang, Feng-Hua.,Al-Safi, Rasha I..,Zeng, Li-Fan.,Shabaik, Yumna.,...&Long, Ya-Qiu.(2011).Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: A scaffold hopping approach using salicylate and catechol groups.BIOORGANIC & MEDICINAL CHEMISTRY,19(16),4935-4952.
MLA Fan, Xing,et al."Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: A scaffold hopping approach using salicylate and catechol groups".BIOORGANIC & MEDICINAL CHEMISTRY 19.16(2011):4935-4952.

入库方式： OAI收割

来源：上海药物研究所

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