NCRR: UCSC Integrated Small Molecule Screening Facility

NCRR：UCSC 集成小分子筛选设施

• 批准号: 7221719
• 负责人: Robert SCOTT LOKEY
• 金额: $ 50万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7221719
• 关键词: Actins; Arts; Biological Factors; Biological Process; Cell Cycle Checkpoint; Collection; Cytokinesis; Devices; Disease; Drug Delivery Systems; Equipment; Goals; Housing; Industry; Infection; Inflammation; Lead; Libraries; Lipoxygenase; Liquid substance; Malaria; Manuals; Microbial Biofilms; National Center for Research Resources; Operative Surgical Procedures; Pharmaceutical Preparations; Play; Public Sector; RNA Splicing; Research; Research Personnel; Role; Screening procedure; Speed; Techniques; Therapeutic; Time; Transcription Elongation; United States National Institutes of Health; Validation; base; cell growth; chromatin remodeling; high throughput screening; novel; programs; small molecule

DESCRIPTION (provided by applicant): The discovery of bioactive small molecules has emerged as a major theme in academic research and is central to the NIH Roadmap initiative. Using modest equipment and a unique collection of natural and synthetic compounds, we have established a vibrant small molecule screening program at UCSC that has yielded fruitful results. Our current screening throughput, however, is far too slow to keep pace with our expanding compound collection. The Crews lab's natural product collection has grown substantially with the recent implementation of new high-throughput purification techniques, and the acquisition of commercial and private compound libraries will bring our total in-house collection to more than 50,000 by the end of this year. Our current screening lab consists of a manual compound transfer device and low throughput liquid handling equipment capable of performing operations on one plate at a time. This proposal is to request high-throughput screening (HTS) equipment for the establishment of a state-of-the-art screening facility at UCSC. Based on the screens proposed, this facility will lead to the identification of novel small molecule probes of the following biological processes: cell cycle checkpoints, cell growth, RNA splicing, transcription elongation, chromatin remodeling, inflammation (due to lipoxygenase activity), actin dynamics, bacterial biofilm formation, malaria infection, and cytokinesis. The creation of a modern HTS facility at UCSC will thus facilitate the discovery of potential therapeutic leads and drug targets related to a variety of disease states. Relevance: High throughput screening is expected to have a major impact in small molecule probe discovery in the public sector just as it has played a role in speeding up drug lead discovery in industry. In order to bring this goal to fruition, integrated HTS equipment must be available to researchers for the validation and implementation of screens in high throughput format.

描述（由申请人提供）：生物活性小分子的发现已经成为学术研究的一个主要主题，并且是NIH路线图计划的核心。使用适度的设备和天然和合成化合物的独特集合，我们已经在UCSC建立了一个充满活力的小分子筛选计划，并取得了丰硕的成果。然而，我们目前的筛选通量太慢，无法跟上我们不断扩大的化合物收集的步伐。Crews实验室的天然产物收藏随着最近新的高通量纯化技术的实施而大幅增长，收购商业和私人化合物库将使我们的内部收藏总量在今年年底前超过50，000。我们目前的筛选实验室包括一个手动化合物转移装置和低通量液体处理设备，能够一次在一个板上进行操作。该提案要求高通量筛选（HTS）设备，以在UCSC建立最先进的筛选设施。基于提出的筛选，该设施将导致以下生物过程的新型小分子探针的鉴定：细胞周期检查点，细胞生长，RNA剪接，转录延长，染色质重塑，炎症（由于脂氧合酶活性），肌动蛋白动力学，细菌生物膜形成，疟疾感染和胞质分裂。因此，在UCSC创建现代HTS设施将有助于发现与各种疾病状态相关的潜在治疗线索和药物靶点。相关性：高通量筛选预计将对公共部门的小分子探针发现产生重大影响，就像它在加速工业中的药物先导发现中发挥作用一样。为了实现这一目标，必须向研究人员提供集成HTS设备，以验证和实施高通量格式的筛选。

项目成果

Conformation and Permeability: Cyclic Hexapeptide Diastereomers.

• DOI: 10.1021/acs.jcim.9b00217
• 发表时间: 2019-06-24
• 期刊: Journal of chemical information and modeling
• 影响因子: 5.6
• 作者: Ono S;Naylor MR;Townsend CE;Okumura C;Okada O;Lokey RS
• 通讯作者: Lokey RS

A Strategy for Direct Chemical Activation of the Retinoblastoma Protein.

视网膜母细胞瘤蛋白的直接化学激活策略。

• DOI: 10.1021/acschembio.6b00011
• 发表时间: 2016
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Pye,CameronR;Bray,WalterM;Brown,EliseR;Burke,JasonR;Lokey,RScott;Rubin,SethM
• 通讯作者: Rubin,SethM

"Function-first" lead discovery: mode of action profiling of natural product libraries using image-based screening.

• DOI: 10.1016/j.chembiol.2012.12.007
• 发表时间: 2013-02-21
• 期刊: Chemistry & biology
• 作者: Schulze CJ;Bray WM;Woerhmann MH;Stuart J;Lokey RS;Linington RG
• 通讯作者: Linington RG

Large-scale cytological profiling for functional analysis of bioactive compounds.

用于生物活性化合物功能分析的大规模细胞学分析。

• DOI: 10.1039/c3mb70245f
• 发表时间: 2013
• 期刊: Molecular bioSystems
• 作者: Woehrmann,MarcosH;Bray,WalterM;Durbin,JamesK;Nisam,SeanC;Michael,AliciaK;Glassey,Emerson;Stuart,JoshuaM;Lokey,RScott
• 通讯作者: Lokey,RScott

Drug-Like Properties in Macrocycles above MW 1000: Backbone Rigidity versus Side-Chain Lipophilicity.

• DOI: 10.1002/anie.202004550
• 发表时间: 2020-11-23
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Furukawa A;Schwochert J;Pye CR;Asano D;Edmondson QD;Turmon AC;Klein VG;Ono S;Okada O;Lokey RS
• 通讯作者: Lokey RS