Cofactor-Independent Phosphoglycerate Mutase from Nematodes Has Limited Druggability, as Revealed by Two High-Throughput Screens
文献类型：期刊论文
| 作者 | Crowther, Gregory J.3; Booker, Michael L.1; He, Min4; Li, Ting4; Raverdy, Sylvine2; Novelli, Jacopo F.2; He, Panqing3; Dale, Natalie R. G.3; Fife, Amy M.1; Barker, Robert H.1 |
| 刊名 | PLOS NEGLECTED TROPICAL DISEASES
 |
| 出版日期 | 2014-01 |
| 卷号 | 8期号:1 |
| ISSN号 | 1935-2735 |
| DOI | 10.1371/journal.pntd.0002628 |
| 文献子类 | Article |
| 英文摘要 | Cofactor-independent phosphoglycerate mutase (iPGAM) is essential for the growth of C. elegans but is absent from humans, suggesting its potential as a drug target in parasitic nematodes such as Brugia malayi, a cause of lymphatic filariasis (LF). iPGAM's active site is small and hydrophilic, implying that it may not be druggable, but another binding site might permit allosteric inhibition. As a comprehensive assessment of iPGAM's druggability, high-throughput screening (HTS) was conducted at two different locations: similar to 220,000 compounds were tested against the C. elegans iPGAM by Genzyme Corporation, and similar to 160,000 compounds were screened against the B. malayi iPGAM at the National Center for Drug Screening in Shanghai. iPGAM's catalytic activity was coupled to downstream glycolytic enzymes, resulting in NADH consumption, as monitored by a decline in visible-light absorbance at 340 nm. This assay performed well in both screens (Z'-factor >0.50) and identified two novel inhibitors that may be useful as chemical probes. However, these compounds have very modest potency against the B. malayi iPGAM (IC50 >10 mu M) and represent isolated singleton hits rather than members of a common scaffold. Thus, despite the other appealing properties of the nematode iPGAMs, their low druggability makes them challenging to pursue as drug targets. This study illustrates a "druggability paradox" of target-based drug discovery: proteins are generally unsuitable for resource-intensive HTS unless they are considered druggable, yet druggability is often difficult to predict in the absence of HTS data. |
| WOS关键词 | DRUG DISCOVERY ; BACILLUS-STEAROTHERMOPHILUS ; PLASMODIUM-FALCIPARUM ; CATALYTIC MECHANISM ; NEGLECTED DISEASES ; TRYPANOSOMA-BRUCEI ; CRYSTAL-STRUCTURE ; INHIBITORS ; IDENTIFICATION ; PREDICTION |
| 资助项目 | World Health Organization's Special Programme for Research and Training in Tropical Diseases (WHO/TDR)[00000000] ; NIH grants[AI080625] ; NIH grants[AI089441] ; New England Biolabs[00000000] ; Ministry of Science and Technology of China[2010DFB73280] |
| WOS研究方向 | Infectious Diseases ; Parasitology ; Tropical Medicine |
| 语种 | 英语 |
| WOS记录号 | WOS:000337977300027 |
| 出版者 | PUBLIC LIBRARY SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277283]  |
| 专题 | 国家新药筛选中心 |
| 通讯作者 | Crowther, Gregory J. |
| 作者单位 | 1.Genzyme Corp, Waltham, MA USA; 2.New England Biolabs Inc, Div Parasitol, Ipswich, MA USA 3.Univ Washington, Div Allergy & Infect Dis, Seattle, WA 98195 USA; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 200031, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Crowther, Gregory J.,Booker, Michael L.,He, Min,et al. Cofactor-Independent Phosphoglycerate Mutase from Nematodes Has Limited Druggability, as Revealed by Two High-Throughput Screens[J]. PLOS NEGLECTED TROPICAL DISEASES,2014,8(1). |
| APA | Crowther, Gregory J..,Booker, Michael L..,He, Min.,Li, Ting.,Raverdy, Sylvine.,...&Wang, Ming-Wei.(2014).Cofactor-Independent Phosphoglycerate Mutase from Nematodes Has Limited Druggability, as Revealed by Two High-Throughput Screens.PLOS NEGLECTED TROPICAL DISEASES,8(1). |
| MLA | Crowther, Gregory J.,et al."Cofactor-Independent Phosphoglycerate Mutase from Nematodes Has Limited Druggability, as Revealed by Two High-Throughput Screens".PLOS NEGLECTED TROPICAL DISEASES 8.1(2014). |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。