The Comprehensive Center for Chemical Probe Discovery and Optimization at Scripps

斯克里普斯化学探针发现和优化综合中心

• 批准号: 8525448
• 负责人: HUGH ROSEN
• 金额: $ 786.6万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525448
• 关键词: Affinity; Automation; Binding; Biochemical; Biochemical Pathway; Biological Assay; Biology; Cells; Chemicals; Chemistry; Collection; DNA; Databases; Detection; Development; Enzymes; Florida; Fluorescence Resonance Energy Transfer; Home environment; Hydrolase; Information Technology; Insecta; Ions; Isomerase; Kinetics; Libraries; Ligase; Lyase; Mammalian Cell; Membrane Potentials; Molecular; Molecular Bank; Molecular Target; Oxidoreductase; Parasites; Pharmaceutical Chemistry; Pharmaceutical Preparations; Production; Protein Conformation; Proteins; PubChem; Quality Control; RNA; Reporter Genes; Reporting; Research Institute; Sampling; Screening Result; Second Messenger Systems; System; Testing; Toxic effect; Transferase; United States National Institutes of Health; Writing; Yeasts; base; cheminformatics; drug discovery; drug market; high throughput screening; protein protein interaction; receptor; repository; screening; second messenger; small molecule; transcription factor

High Throughput Screening (HTS) leverages automation, chemistry, biology and information technologies to rapidly assay the pharmacologic activity of drug-like molecules. As applied to drug discovery, it has been successful for discovering the precursors of marketed drugs as well as probes of various cellular and biochemical pathways. Scripps Florida is the home of the ¿ultra¿ HTS (uHTS) Implementation core of the Scripps Research Institute Molecular Screening Center (SRIMSC). Core staff are responsible for developing and implementing the SRIMSC¿s screening assays, managing the Molecular Libraries Small Molecule Repository (MLSMR) screening collection of >360,000 samples, screening the MLSMR library at a throughput in excess of 1 million samples per day, quality control & reporting of all screening results to the NIH¿s publically available database (PubChem), cheminformatics support and overall project management for the SRIMSC. The core sustains full production capabilities for the NIH by screening the entire MLSMR compound library against more than 25 unique targets per year. As of this writing core staff have completed more than 185 high throughput screening campaigns for 175 molecular targets, with more than 40 million wells tested. Staff also execute lower-throughput bioassays to support the SRIMSC¿s hit-to-probe medicinal chemistry efforts, participating in more than 50 probe development projects per year. Target classes screened by the core include receptors, transcription factors, transferases, hydrolases, oxidoreductases, lyases, isomerases and ligases; protein interactions (protein-protein, protein-DNA, and protein-RNA) and phenotypic bioassays. Targets have been purified for screening (e.g. enzymes or proteins) or assayed in whole-cell mammalian, bacterial, insect, yeast/fungal, and parasite systems. Screening formats include biochemical enzymatic & binding affinity assays, as well as whole-cell reporter gene, second messenger, membrane potential, ion flux, complementation, protein conformation, renaturation and toxicity assays. A variety of plate-based detection formats including kinetic (FLIPR, Alphascreen, TR-FRET, FP etc.) and high content analysis (HCA) are utilized for screening efforts. More information can be found at: http://hts.florida.scripps.edu/

高吞吐量筛选（HTS）利用自动化，化学，生物学和信息技术来迅速主张药物样分子的药物活性。正如用于药物发现的那样，它已经成功地发现了销售药物的前体以及各种细胞和生化途径的问题。 Scripps Florida是Scripps研究所分子筛查中心（SRIMSC）的Ultra hts（UHTS）实施核心的所在地。核心人员负责开发和实施SRIMSC筛查测定法，管理分子库小分子储存库（MLSMR）筛选> 360,000个样本的筛选集合，并以超过100万个样本的范围筛选MLSMR库，以每天超过100万个样本的质量控制和报告的质量控制和报告（公共质量数据），并公开了nih的质量控制和公开范围。 SRIMSC。 通过筛选整个MLSMR化合物库每年超过25个独特的目标，核心维护将为NIH提供全面的生产能力。在此写作时，核心人员已经完成了175个分子目标的185多个高通量筛选活动，并进行了超过4000万井的测试。员工还执行低通量的生物测定法，以支持SRIMSC的热门探针化学努力，每年参加50多个探针开发项目。 由核心筛选的目标类别包括受体，转录因子，转移，水解酶，氧化酶，裂解酶，异构酶和连接酶；蛋白质相互作用（蛋白质 - 蛋白质，蛋白-DNA和蛋白-RNA）和表型生物测定。靶标已被纯化用于筛选（例如酶或蛋白质）或在全细胞哺乳动物，细菌，绝缘，酵母/真菌和寄生虫系统中测定。筛选格式包括生化酶和结合亲和力测定，以及全细胞报告基因，第二信使，膜电位，离子通量，完成，蛋白质构象，肾脏构象，重新饱和和毒性测定。各种基于板的检测格式，包括动力学（FLIPR，Alphascreen，TR-FRET，FP等）和高含量分析（HCA）（HCA）进行筛查。更多信息可以在以下网址找到：http：//hts.florida.scripps.edu/

项目成果

Identification of Potent and Selective Inhibitors of the Plasmodium falciparum M18 Aspartyl Aminopeptidase (PfM18AAP) of Human Malaria via High-Throughput Screening.

• DOI: 10.1177/1087057114525852
• 发表时间: 2014-08
• 期刊: Journal of biomolecular screening
• 作者: Spicer T;Fernandez-Vega V;Chase P;Scampavia L;To J;Dalton JP;Da Silva FL;Skinner-Adams TS;Gardiner DL;Trenholme KR;Brown CL;Ghosh P;Porubsky P;Wang JL;Whipple DA;Schoenen FJ;Hodder P
• 通讯作者: Hodder P

A high-throughput screening compatible assay for activators and inhibitors of methionine sulfoxide reductase A.

• DOI: 10.1089/adt.2009.0263
• 发表时间: 2010-10
• 期刊: Assay and drug development technologies
• 影响因子: 1.8
• 作者: David Brunell;H. Weissbach;P. Hodder;N. Brot

An altered zinc-binding site confers resistance to a covalent inactivator of New Delhi metallo-beta-lactamase-1 (NDM-1) discovered by high-throughput screening.

• DOI: 10.1016/j.bmc.2013.03.031
• 发表时间: 2013-06-01
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Thomas, Pei W.;Spicer, Timothy;Cammarata, Michael;Brodbelt, Jennifer S.;Hodder, Peter;Fast, Walter
• 通讯作者: Fast, Walter

Preparation of tetrasubstituted pyrimido[4,5-d]pyrimidine diones.

四取代嘧啶并[4,5-d]嘧啶二酮的制备。

• DOI: 10.1016/j.tetlet.2015.02.051
• 发表时间: 2015
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Wang,Hui;Wang,Chao;Bannister,ThomasD
• 通讯作者: Bannister,ThomasD

Identification of small molecules that disrupt signaling between ABL and its positive regulator RIN1.

• DOI: 10.1371/journal.pone.0121833
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ting PY;Damoiseaux R;Titz B;Bradley KA;Graeber TG;Fernández-Vega V;Bannister TD;Chase P;Nair R;Scampavia L;Hodder P;Spicer TP;Colicelli J
• 通讯作者: Colicelli J