Novel fatty acid binding protein 4 (FABP4) inhibitors: Virtual screening, synthesis and crystal structure determination
文献类型：期刊论文
| 作者 | Cai, Haiyan2,3; Liu, Qiufeng1,2; Gao, Dingding4; Wang, Ting2; Chen, Tiantian2; Yan, Guirui2; Chen, Kaixian2 ; Xu, Yechun2; Wang, Heyao2; Li, Yingxia4
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2015-01-27 |
| 卷号 | 90页码:241-250 |
| ISSN号 | 0223-5234 |
| 关键词 | FABP4 Inhibitor Diabetes Virtual screening Crystal structure |
| DOI | 10.1016/j.ejmech.2014.11.020 |
| 文献子类 | Article |
| 英文摘要 | Fatty acid binding protein 4 (FABP4) is a potential drug target for diabetes and atherosclerosis. For discovering new chemical entities as FABP4 inhibitors, structure-based virtual screening (VS) was performed, bioassay demonstrated that 16 of 251 tested compounds are FABP4 inhibitors, among which compound m1 are more active than endogenous ligand linoleic acid (LA). Based on the structure of m1, new derivatives were designed and prepared, leading to the discovery of two more potent inhibitors, compounds 9 and 10. To further explore the binding mechanisms of these new inhibitors, we determined the X-ray structures of the complexes of FABP4-9 and FABP4-10, which revealed similar binding conformations of the two compounds. Residue Ser53 and Arg126 formed direct hydrogen bonding with the ligands. We also found that 10 could significantly reduce the levels of lipolysis on mouse 3T3-L1 adipocytes. Taken together, in silico, in vitro and crystallographic data provide useful hints for future development of novel inhibitors against FABP4. (C) 2014 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | AP2 ; MICE ; ATHEROSCLEROSIS ; EXPRESSION ; DOCKING ; GLUCOSE ; OBESITY ; GENE |
| 资助项目 | National Natural Science Foundation of China[81302699] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2012ZX09301-001-004] ; National 863 High Performance Computing Project[2012AA01A305] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| WOS记录号 | WOS:000348951900019 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276665]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Xu, Yechun |
| 作者单位 | 1.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; 3.Shanghai Jiao Tong Univ, Dept Pathophysiol, Chinese Minist Educ, Key Lab Cell Differentiat & Apoptosis,Sch Med, Shanghai 200030, Peoples R China; 4.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Cai, Haiyan,Liu, Qiufeng,Gao, Dingding,et al. Novel fatty acid binding protein 4 (FABP4) inhibitors: Virtual screening, synthesis and crystal structure determination[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2015,90:241-250. |
| APA | Cai, Haiyan.,Liu, Qiufeng.,Gao, Dingding.,Wang, Ting.,Chen, Tiantian.,...&Zhu, Weiliang.(2015).Novel fatty acid binding protein 4 (FABP4) inhibitors: Virtual screening, synthesis and crystal structure determination.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,90,241-250. |
| MLA | Cai, Haiyan,et al."Novel fatty acid binding protein 4 (FABP4) inhibitors: Virtual screening, synthesis and crystal structure determination".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 90(2015):241-250. |
入库方式： OAI收割
来源：上海药物研究所
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