Identification of a novel selective PPAR gamma ligand with a unique binding mode and improved therapeutic profile in vitro
文献类型：期刊论文
| 作者 | Yi, Wei2,3; Shi, Jingjing2 ; Zhao, Guanguan2; Zhou, X. Edward1; Suino-Powell, Kelly1; Melcher, Karsten1; Xu, H. Eric1,2
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| 刊名 | Scientific Reports
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| 出版日期 | 2017-01-27 |
| 卷号 | 7 |
| ISSN号 | 2045-2322 |
| DOI | 10.1038/srep41487 |
| 文献子类 | Article |
| 英文摘要 | Thiazolidinediones (TZD) function as potent anti-diabetic drugs through their direct action on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma), but their therapeutic benefits are compromised by severe side effects. To address this concern, here we developed a potent "hit" compound, VSP-51, which is a novel selective PPAR gamma-modulating ligand with improved therapeutic profiles in vitro compared to the multi-billion dollar TZD drug rosiglitazone (Rosi). Unlike Rosi, VSP-51 is a partial agonist of PPAR gamma with improved insulin sensitivity due to its ability to bind PPAR gamma with high affinity without stimulating adipocyte differentiation and the expression of adipogenesis-related genes. We have determined the crystal structure of the PPAR gamma ligand-binding domain (LBD) in complex with VSP-51, which revealed a unique mode of binding for VSP-51 and provides the molecular basis for the discrimination between VSP-51 from TZDs and other ligands such as telmisartan, SR1663 and SR1664. Taken together, our findings demonstrate that: a) VSP-51 can serve as a promising candidate for antidiabetic drug discovery; and b) provide a rational basis for the development of future pharmacological agents targeting PPAR gamma with advantages over current TZD drugs. |
| WOS关键词 | ACTIVATED RECEPTOR-GAMMA ; TYPE-2 DIABETES-MELLITUS ; NUCLEAR RECEPTORS ; PARTIAL AGONISTS ; MECHANISM ; THIAZOLIDINEDIONES ; ROSIGLITAZONE ; INSIGHTS ; STIMULATION ; TELMISARTAN |
| 资助项目 | Jay and Betty Van Andel Foundation[00000000] ; Amway (China)[00000000] ; Youth Innovation Promotion Association CAS[00000000] ; Shanghai Municipal Natural Science Foundation, China[15ZR1447800] ; NSFC[81502909] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120152031] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000393164800001 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275668]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Yi, Wei; Xu, H. Eric |
| 作者单位 | 1.Van Andel Res Inst, Program Struct Biol & Drug Discovery, Lab Struct Sci, Grand Rapids, MI 49503 USA 2.Chinese Acad Sci, Ctr Struct & Funct Drug Targets, CAS Key Lab Receptor Res, VARI SIMM Ctr,Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 3.Guangzhou Med Univ, Sch Pharmaceut Sci, Guangzhou 511436, Guangdong, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Yi, Wei,Shi, Jingjing,Zhao, Guanguan,et al. Identification of a novel selective PPAR gamma ligand with a unique binding mode and improved therapeutic profile in vitro[J]. Scientific Reports,2017,7. |
| APA | Yi, Wei.,Shi, Jingjing.,Zhao, Guanguan.,Zhou, X. Edward.,Suino-Powell, Kelly.,...&Xu, H. Eric.(2017).Identification of a novel selective PPAR gamma ligand with a unique binding mode and improved therapeutic profile in vitro.Scientific Reports,7. |
| MLA | Yi, Wei,et al."Identification of a novel selective PPAR gamma ligand with a unique binding mode and improved therapeutic profile in vitro".Scientific Reports 7(2017). |
入库方式： OAI收割
来源：上海药物研究所
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