Building Libraries with Chemical Diversity for Screening

我们与四个NIGMS资助的CMLD中的三个（波士顿大学，堪萨斯大学和匹兹堡大学）建立了材料转移协议（MTA）。这三个中心提供了超过10，000个已知结构的样本。每个CMLD都有不同的库设计方法，因此它们的库之间的重叠可以忽略不计。MTL随后与其他学术和工业合作伙伴签订了许多协议，以增加我们图书馆的广度。与传统药物化学团体的合作值得注意的是清华大学的刘刚教授和罗马大学的Roberto DiSanto教授。此外，我们已经获得了一些重点化合物集，包括LOPAC，Glaxo Smith Kline激酶库，BioMol Natural Products和ICCB Known Bioactive。作为美国国务院资助的减少威胁方案的一部分，鼓励哈萨克斯坦Stepnogorsk前生物武器设施的科学家探索非生物武器科学领域。该计划在哈萨克斯坦阿拉木图的国际科学技术中心（ISTC）的保护下进行。MTL的工作人员曾四次前往哈萨克斯坦开展这项合作，最近收到了延长两年的通知。我们组织了集中于哈萨克斯坦特有的800种植物的收集。到目前为止，我们已经收集了超过一百种植物标本;植物提取物已经在NCI 60细胞筛选中进行了测试，并在MTL筛选中进行了预分级测试。通过与两位韩国访问科学家Young Ho Kim博士（韩国大田忠南国立大学）和Ik Soo Lee博士（韩国光州忠南国立大学）的合作，我们获得了大量的韩国植物提取物。我们与这些实验室的持续合作使我们能够获得大量纯化的植物天然产物。耶鲁大学的Scott Strobel博士获得了真菌内生菌提取物的独特资源。内生菌已培养从秘鲁植物在本科班。学生们安排在耶鲁大学进行生物学测试，然后分离出活性天然产物。耶鲁大学的分子测试确保了培养物的独特性。本沈博士（斯克里普斯佛罗里达）的实验室专门从事放线菌的分子遗传学，特别是非核糖体肽和聚酮合酶系统。沈实验室还积极探索刺激隐蔽生物合成基因表达的方法。通过与Shen实验室的合作，我们获得了数百种具有明确遗传学的放线菌提取物和一些纯化合物。从生物合成途径的遗传操作中获得的化合物在MTL筛选项目中提供了结构-活性信息。MTL最近收购了Matrical MiniStore，这是一种用于存储和检索2D条形码试管和平板的集成机器人系统。自动化的样品储存大大提高了我们快速挑选HTS初步测定中发现的命中物的能力，以确认活性和进行二次生物学评价。目前，该系统拥有180，703管和967板。在过去的4年里，CDDS开发了一个定制的基于Web的分析和样品管理系统，使我们的研究人员能够管理样品库，设计分析板，存储和分析生物测定数据。

We established of Material Transfer Agreements (MTA) with three of the four NIGMS-funded CMLDs (Boston University, the University of Kansas, and the University of Pittsburgh). These three centers have provided over 10,000 samples of known structure. Each CMLD has a distinct approach to library design, thus there is negligible overlap between their libraries. The MTL has subsequently entered into numerous agreements with other academic and industrial partners to increase the breadth of our libraries. Notable collaborations with traditional medicinal chemistry groups are with Prof. Gang Liu of Tsinghua University, and Prof. Roberto DiSanto of the University of Rome. Furthermore, we have obtained a number of focused compound sets, including LOPAC, the Glaxo Smith Kline kinase library, BioMol Natural Products, and ICCB Known Bioactives. As part of a US State Department-funded threat reduction program, scientists at the former bioweapons (BW) facility in Stepnogorsk, Kazakhstan have been encouraged to explore non-BW scientific horizons. The program is conducted under the umbrella of the International Science and Technology Center (ISTC), in Almaty, Kazakhstan. MTL staff traveled to Kazakhstan on four occasions to develop this collaboration, which recently received notice of renewal for two more years. We have organized plant collections focused on the 800 species endemic to Kazakhstan. To date, we have collected over a hundred plant specimens; the plant extracts have been tested in the NCI 60 cell screen and prefractionated for testing in MTL screens.Through collaboration with two Korean visiting scientists, Dr. Young Ho Kim (Chungnam National University, Daejon, Korea) and Dr. Ik Soo Lee (Chonnam National University, Gwangju, Korea), we obtained an extensive collection of Korean plant extracts. Our ongoing collaboration with these laboratories has enabled us to receive a large collection of purified plant natural products as well.A unique resource of fungal endophyte extracts has been obtained from Dr. Scott Strobel at Yale University. The endophytes have been cultured from Peruvian plants in an undergraduate class. The students arrange for biological testing at Yale and then isolate active natural products. Molecular testing at Yale ensures that the cultures are distinct. The laboratory of Dr. Ben Shen (Scripps Florida) specializes in the molecular genetics of actinomycetes, particularly non-ribosomal peptide and polyketide synthase systems. The Shen lab is also active in discovering means for stimulating expression of cryptic biosynthetic genes. Through collaboration with the Shen laboratory we have obtained access to hundreds of actinomycete extracts with well defined genetics, and a number of pure compounds. Compounds obtained from genetic manipulation of the biosynthetic pathways have provided structure-activity information in an MTL screening project. The MTL recently acquired a Matrical MiniStore, an integrated robotic system for storing and retrieving both 2D bar coded tubes and plates. Automated sample storage has dramatically increased our ability to rapidly cherry pick hits found in HTS primary assays for confirmation of activity and for secondary biological evaluation. Currently the system holds 180,703 tubes and 967 plates. Over the past 4 years, the CDDS has developed a customized web based assay and sample management system which allows our researchers to manage sample libraries, design assay plates and store and analyze bioassay data.