Current chemical genomics最新文献_第3页

Drug discovery toward antagonists of methyl-lysine binding proteins. 发现甲基赖氨酸结合蛋白拮抗剂的药物。

Current chemical genomics Pub Date : 2011-01-01 Epub Date: 2011-08-22 DOI: 10.2174/1875397301005010051

J Martin Herold, Lindsey A Ingerman, Cen Gao, Stephen V Frye

引用次数: 0

An automated approach to efficiently reformat a large collection of compounds. 一种自动化的方法，可以有效地重新格式化大量化合物。

Current chemical genomics Pub Date : 2011-01-01 Epub Date: 2011-07-22 DOI: 10.2174/1875397301105010042

Jimmy Cui, Sergio C Chai, Anang A Shelat, R Kiplin Guy, Taosheng Chen

引用次数: 5

NRF2 Oxidative Stress Induced by Heavy Metals is Cell Type Dependent. 重金属诱导的NRF2氧化应激具有细胞类型依赖性。

Current chemical genomics Pub Date : 2011-01-01 Epub Date: 2011-01-06 DOI: 10.2174/1875397301105010001

Steven O Simmons, Chun-Yang Fan, Kim Yeoman, John Wakefield, Ram Ramabhadran

{"title":"NRF2 Oxidative Stress Induced by Heavy Metals is Cell Type Dependent.","authors":"Steven O Simmons, Chun-Yang Fan, Kim Yeoman, John Wakefield, Ram Ramabhadran","doi":"10.2174/1875397301105010001","DOIUrl":"https://doi.org/10.2174/1875397301105010001","url":null,"abstract":"Exposure to metallic environmental toxicants has been demonstrated to induce a variety of oxidative stress responses in mammalian cells. The transcription factor Nrf2 is activated in response to oxidative stress and coordinates the expression of antioxidant gene products. In this study, we describe the development of an Nrf2-specific reporter gene assay that can be used to study the oxidative stress response in multiple cell types. Using five different cell lines, the Nrf2-activating potency of twenty metals was assessed across a range of concentrations. While ten of the metals tested (cadmium, cobalt, copper, gold, iron, lead, mercury, silver, sodium arsenite and zinc) stimulated Nrf2-dependent transcriptional activity in at least three of the engineered cell lines, only three (cadmium, copper and sodium arsenite) were active in all five cell lines. A comparison of metal-induced Nrf2 transcriptional activation revealed significant differences in the absolute magnitude of activation as well as the relative potencies between the cell lines tested. However, there was no direct correlation between activity and potency. Taken together, these results show that the capacity to stimulate Nrf2 activity and relative potencies of these test compounds are highly dependent on the cell type tested. Since oxidative stress is thought to be involved in the mode of action of many toxicological studies, this observation may inform the design of paradigms for toxicity testing for toxicant prioritization and characterization.","PeriodicalId":88232,"journal":{"name":"Current chemical genomics","volume":"5 ","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9d/32/TOCHGENJ-5-1.PMC3106370.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29915743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 111

A High Throughput Assay for Discovery of Bacterial β-Glucuronidase Inhibitors. 发现细菌β-葡萄糖醛酸酶抑制剂的高通量测定。

Current chemical genomics Pub Date : 2011-01-01 Epub Date: 2011-04-08 DOI: 10.2174/1875397301105010013

Syed Ahmad, Mark A Hughes, Kimberly T Lane, Matthew R Redinbo, Li-An Yeh, John E Scott

{"title":"A High Throughput Assay for Discovery of Bacterial β-Glucuronidase Inhibitors.","authors":"Syed Ahmad, Mark A Hughes, Kimberly T Lane, Matthew R Redinbo, Li-An Yeh, John E Scott","doi":"10.2174/1875397301105010013","DOIUrl":"https://doi.org/10.2174/1875397301105010013","url":null,"abstract":"CPT-11 is a widely-used anti-cancer drug that is converted in vivo to its active metabolite, SN-38. In the liver, enzymes detoxify SN-38 by coupling it to a glucuronidate moiety and this inactive compound (SN-38G) is excreted into the gastrointestinal tract. In the intestine, commensal bacteria convert the SN-38G back to the active and toxic SN-38 using bacterial β-glucuronidase enzyme (GUS). This intestinal SN-38 causes debilitating diarrhea that prevents dose-intensification and efficacy in a significant fraction of patients undergoing CPT-11 treatment for cancer. This CPT-11 metabolic pathway suggests that small molecule inhibitors of GUS may have utility as novel therapeutics for prevention of dose-limiting diarrhea resulting from CPT-11 therapy. To identify chemical inhibitors of GUS activity, we employed and validated a high throughput, fluorescence-based biochemical assay and used this assay to screen a compound library. Novel inhibitors of GUS were identified with IC(50) values ranging from 50 nM to 4.8 µM. These compounds may be useful as chemical probes for use in proof-of-concept experiments designed to determine the efficacy of GUS inhibitors in altering the intestinal metabolism of drugs. Our results demonstrate that this high throughput assay can be used to identify small molecule inhibitors of GUS.","PeriodicalId":88232,"journal":{"name":"Current chemical genomics","volume":"5 ","pages":"13-20"},"PeriodicalIF":0.0,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/74/73/TOCHGENJ-5-13.PMC3106358.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29915744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 23

Promoting illiteracy in epigenetics: an emerging therapeutic strategy. 促进表观遗传学文盲:一种新兴的治疗策略。

Current chemical genomics Pub Date : 2011-01-01 Epub Date: 2011-08-22 DOI: 10.2174/1875397301005010048

Tim J Wigle

引用次数: 6

Structural Chemistry of Human SET Domain Protein Methyltransferases. 人类 SET 结构域蛋白甲基转移酶的结构化学。

Current chemical genomics Pub Date : 2011-01-01 Epub Date: 2011-08-22 DOI: 10.2174/1875397301005010085

Matthieu Schapira

引用次数: 0

A cell-based protein-protein interaction method using a permuted luciferase reporter. 一种基于细胞的蛋白-蛋白相互作用方法，使用排列荧光素酶报告基因。

Current chemical genomics Pub Date : 2011-01-01 Epub Date: 2011-11-30 DOI: 10.2174/1875397301105010122

Haifeng Eishingdrelo, Jidong Cai, Paul Weissensee, Praveen Sharma, Michael J Tocci, Paul S Wright

引用次数: 20

Catalytic specificity of human protein tyrosine kinases revealed by Peptide substrate profiling. 肽底物分析揭示的人蛋白酪氨酸激酶的催化特异性。

Current chemical genomics Pub Date : 2011-01-01 Epub Date: 2011-08-22 DOI: 10.2174/1875397301105010115

Julie Blouin, Philippe Roby, Mathieu Arcand, Lucille Beaudet, Francesco Lipari

引用次数: 9

Luciferase Reporter Assay System for Deciphering GPCR Pathways. 解读GPCR途径的荧光素酶报告基因检测系统。

Current chemical genomics Pub Date : 2010-12-21 DOI: 10.2174/1875397301004010084

Zhijie Cheng, Denise Garvin, Aileen Paguio, Pete Stecha, Keith Wood, Frank Fan

{"title":"Luciferase Reporter Assay System for Deciphering GPCR Pathways.","authors":"Zhijie Cheng, Denise Garvin, Aileen Paguio, Pete Stecha, Keith Wood, Frank Fan","doi":"10.2174/1875397301004010084","DOIUrl":"https://doi.org/10.2174/1875397301004010084","url":null,"abstract":"The G protein coupled receptors (GPCR) represent the target class for nearly half of the current therapeutic drugs and remain to be the focus of drug discovery efforts. The complexity of receptor signaling continues to evolve. It is now known that many GPCRs are coupled to multiple G-proteins, which lead to regulation of respective signaling pathways downstream. Deciphering this receptor coupling will aid our understanding of the GPCR function and ultimately developing drug candidates. Here, we report the development of four homogenous bioluminescent reporter assays using improved destabilized luciferases and various response elements: CRE, NFAT-RE, SRE, and SRF-RE. These assays allowed measurement of major GPCR pathways including cAMP production, intracellular Ca(2+) mobilizations, ERK/MAPK activ-ity, and small G protein RhoA activity, respectively using the same reporter assay format. We showed that we can decipher G protein activation profiles for exogenous m(3) muscarinic receptor and endogenous β(2)-adrenergic receptors in HEK293 cells by using these four reporter assays. Furthermore, we demonstrated that these assays can be readily used for potency rankings of agonists and antagonists, and for high throughput screening.","PeriodicalId":88232,"journal":{"name":"Current chemical genomics","volume":"4 ","pages":"84-91"},"PeriodicalIF":0.0,"publicationDate":"2010-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1875397301004010084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29680987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 147

A rapid, inexpensive high throughput screen method for neurite outgrowth. 一种快速、廉价、高通量的神经突生长筛选方法。

Current chemical genomics Pub Date : 2010-12-13 DOI: 10.2174/1875397301004010074

Susan T Yeyeodu, Sam M Witherspoon, Nailya Gilyazova, Gordon C Ibeanu

{"title":"A rapid, inexpensive high throughput screen method for neurite outgrowth.","authors":"Susan T Yeyeodu, Sam M Witherspoon, Nailya Gilyazova, Gordon C Ibeanu","doi":"10.2174/1875397301004010074","DOIUrl":"https://doi.org/10.2174/1875397301004010074","url":null,"abstract":"Neurite outgrowth assays are the most common phenotypic screen to assess chemical effects on neuronal cells. Current automated assays involve expensive equipment, lengthy sample preparation and handling, costly reagents and slow rates of data acquisition and analysis. We have developed a high throughput screen (HTS) for neurite outgrowth using a robust neuronal cell model coupled to fast and inexpensive visualization methods, reduced data volume and rapid data analysis. Neuroscreen-1 (NS-1) cell, a subclone of PC12, possessing rapid growth and enhanced sensitivity to NGF was used as a model neuron. This method reduces preparation time by using cells expressing GFP or native cells stained with HCS CellMask(™) Red in a multiplexed 30 min fixation and staining step. A 2x2 camera binning process reduced both image data files and analysis times by 75% and 60% respectively, compared to current protocols. In addition, eliminating autofocus steps during montage generation reduced data collection time. Pharmacological profiles for stimulation and inhibition of neurite outgrowth by NGF and SU6656 were comparable to current standard method utilizing immunofluorescence detection of tubulin. Potentiation of NGF-induced neurite outgrowth by members of a 1,120-member Prestwick compound library as assayed using this method identified six molecules, including etoposide, isoflupredone acetate, fludrocortisone acetate, thioguanosine, oxyphenbutazone and gibberellic acid, that more than doubled the neurite mass primed by 2 ng/ml NGF. This simple procedure represents an important routine approach in high throughput screening of large chemical libraries using the neurite outgrowth phenotype as a measure of the effects of chemical molecules on neuronal cells.","PeriodicalId":88232,"journal":{"name":"Current chemical genomics","volume":"4 ","pages":"74-83"},"PeriodicalIF":0.0,"publicationDate":"2010-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/37/b2/TOCHGENJ-4-74.PMC3040990.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29693651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 29