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Structure-based design of potent FABP4 inhibitors with high selectivity against FABP3

文献类型：期刊论文

作者Chen, Guofeng3,4,5; Xie, Hang2; Liu, Jiayuan4; Shao, Qiang3,4; Li, Minjun1; Su, Haixia3,4; Xu, Yechun2,3,4,5
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-01-15
卷号264页码:10
关键词Methyl substitution Selectivity FABP4 inhibitor Anti-inflammation Metabolic stability
ISSN号0223-5234
DOI10.1016/j.ejmech.2023.115984
通讯作者Su, Haixia(suhaixia1@simm.ac.cn) ; Xu, Yechun(ycxu@simm.ac.cn)
英文摘要Fatty-acid binding protein 4 (FABP4) presents an attractive target for therapeutic intervention in metabolic and inflammatory diseases in recent years. However, highly similar three-dimensional structures and fatty acid binding ability of multiple FABP family members pose a significant challenge in design of FABP4-selective inhibitors. Particularly, inhibition of FABP3 raises safety concerns such as cardiac dysfunction and exercise intolerance. Here, we reported the discovery of new FABP4 inhibitors with high selectivity over FABP3 by exploiting the little structural difference in the ligand binding pockets of FABP4 and FABP3. On the basis of our previously reported FABP4 inhibitors with nanomolar potency, different substituents were further introduced to perfectly occupy two sub-pockets of FABP4 that are distinct from those of FABP3. Remarkably, a single methyl group introduction leads to the discovery of compound C3 that impressively exhibits a 601-fold selectivity over FABP3 when maintained nanomolar binding affinity for FABP4. Moreover, C3 also shows good metabolic stability and potent cellular anti-inflammatory activity, making it a promising inhibitor for further development. Therefore, the present study highlights the utility of the structure-based rational design strategy for seeking highly selective and potent inhibitors of FABP4 and the importance of identifying the appropriate subsite as well as substituent for gaining the desired selectivity.
WOS关键词ACID-BINDING PROTEIN ; FATTY-ACID ; CRYSTAL-STRUCTURE ; H-FABP ; INTEGRATION ; EXPRESSION ; RESOLUTION ; AFFINITY ; MODEL ; CHAIN
资助项目National Natural Science Foundation of China[22277130] ; Lingang Laboratory[LG-QS-202205-02] ; Science and Technology Commission of Shanghai Municipality[22YF1457300]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001129841900001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/308362]  
专题新药研究国家重点实验室
通讯作者Su, Haixia; Xu, Yechun
作者单位1.Chinese Acad Sci, Shanghai Synchrotron Radiat Facil, Shanghai Adv Res Inst, Shanghai 201210, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Guofeng,Xie, Hang,Liu, Jiayuan,et al. Structure-based design of potent FABP4 inhibitors with high selectivity against FABP3[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,264:10.
APA Chen, Guofeng.,Xie, Hang.,Liu, Jiayuan.,Shao, Qiang.,Li, Minjun.,...&Xu, Yechun.(2024).Structure-based design of potent FABP4 inhibitors with high selectivity against FABP3.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,264,10.
MLA Chen, Guofeng,et al."Structure-based design of potent FABP4 inhibitors with high selectivity against FABP3".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 264(2024):10.

入库方式： OAI收割

来源：上海药物研究所

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