Exploration of Fragment Binding Poses Leading to Efficient Discovery of Highly Potent and Orally Effective Inhibitors of FABP4 for Anti-inflammation

doi:10.1021/acs.jmedchem.9b02107

	Exploration of Fragment Binding Poses Leading to Efficient Discovery of Highly Potent and Orally Effective Inhibitors of FABP4 for Anti-inflammation
	Su, Haixia 1,2; Zou, Yi 1; Chen, Guofeng 1,2; Dou, Huixia 1; Xie, Hang 1; Yuan, Xiaojing 1,2; Zhang, Xianglei 1,2; Zhang, Naixia 2,3; Li, Minjun 4; Xu, Yechun 1,2
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2020-04-23
卷号	63 期号:8 页码:4090-4106
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.9b02107
通讯作者	Xu, Yechun(ycxu@simm.ac.cn)
英文摘要	Fatty-acid binding protein 4 (FABP4) is a promising therapeutic target for immunometabolic diseases, while its potential for systemic inflammatory response syndrome treatment has not been explored. Here, a series of 2-(phenylamino)benzoic acids as novel and potent FABP4 inhibitors are rationally designed based on an interesting fragment that adopts multiple binding poses within FABP4. A fusion of these binding poses leads to the design of compound 3 with an similar to 460-fold improvement in binding affinity compared to the initial fragment. A subsequent structure-aided optimization upon 3 results in a promising lead (17) with the highest binding affinity among all the inhibitors, exerting a significant anti-inflammatory effect in cells and effectively attenuating a systemic inflammatory damage in mice. Our work therefore presents a good example of lead compound discovery derived from the multiple binding poses of a fragment and provides a candidate for development of drugs against inflammation-related diseases.
资助项目	National Key R&D Program of China[2016YFA0502301] ; National Natural Science Foundation of China[81661148046] ; National Natural Science Foundation of China[21877122] ; National Natural Science Foundation of China[21807104] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002]
WOS关键词	PARTICLE MESH EWALD ; FATTY-ACID ; PROTEIN 4 ; APOLIPOPROTEIN-E ; RECEPTOR ; AP2 ; DRUG ; ATHEROSCLEROSIS ; MACROPHAGES ; EXPRESSION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000529170200018
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280598]
专题	中国科学院上海药物研究所
通讯作者	Xu, Yechun
作者单位	1.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, Shanghai 201203, Peoples R China 4.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Su, Haixia,Zou, Yi,Chen, Guofeng,et al. Exploration of Fragment Binding Poses Leading to Efficient Discovery of Highly Potent and Orally Effective Inhibitors of FABP4 for Anti-inflammation[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(8):4090-4106.
APA	Su, Haixia.,Zou, Yi.,Chen, Guofeng.,Dou, Huixia.,Xie, Hang.,...&Xu, Yechun.(2020).Exploration of Fragment Binding Poses Leading to Efficient Discovery of Highly Potent and Orally Effective Inhibitors of FABP4 for Anti-inflammation.JOURNAL OF MEDICINAL CHEMISTRY,63(8),4090-4106.
MLA	Su, Haixia,et al."Exploration of Fragment Binding Poses Leading to Efficient Discovery of Highly Potent and Orally Effective Inhibitors of FABP4 for Anti-inflammation".JOURNAL OF MEDICINAL CHEMISTRY 63.8(2020):4090-4106.