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都有独特的库设计方法，因此它们的库之间的重叠可以忽略。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著名合作是与清华大学刘刚教授和罗马大学Roberto DiSanto教授。此外，我们还获得了许多重点化合物集，包括LOPAC， Glaxo Smith Kline激酶库，BioMol Natural Products, ICCB Known Bioactives，以及来自DCTD， NCI的一系列合成化合物。作为美国国务院资助的减少威胁计划的一部分，位于哈萨克斯坦斯捷普诺戈尔斯克的前生物武器设施的科学家们被鼓励探索非生物武器的科学领域。该项目在哈萨克斯坦阿拉木图的国际科学技术中心（ISTC）的支持下进行。MTL工作人员曾四次前往哈萨克斯坦开展这一合作，最近收到了延长两年的通知。我们组织了植物收集，重点是哈萨克斯坦特有的800种植物。迄今为止，我们收集了超过177个植物标本；植物提取物已在NCI 60细胞筛选中进行了测试，并在MTL筛选中进行了预分离。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（韩国光州全南国立大学）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品。一种独特的真菌内生菌提取物资源已经从耶鲁大学的Scott Strobel博士那里获得。内生菌是从秘鲁植物中培养出来的。学生们安排在耶鲁大学进行生物测试，然后分离出有效的天然产物。耶鲁大学的分子测试确保了文化的独特性。Ben Shen博士（佛罗里达Scripps）的实验室专门研究放线菌的分子遗传学，特别是非核糖体肽和聚酮合成酶系统。沈实验室也积极探索刺激隐性生物合成基因表达的方法。通过与沈实验室的合作，我们已经获得了数百种具有明确遗传学的放线菌提取物和许多纯化合物。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。我们刚刚与布隆伯格研究所合作，这使我们能够访问默克的传统天然产品系列。目前我们的存储系统容纳242465管和1363板。在过去的5年里，CDDS开发了一个定制的基于网络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，设计分析板以及存储和分析生物分析数据。

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, ICCB Known Bioactives, as well as a large series of synthetic compounds from DCTD, NCI. 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 177 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. We have just entered into a collaboration with the Blumberg Institute which has given us access to the Merck legacy natural products collection. Currently our storage system holds 242,465 tubes and 1363 plates. Over the past 5 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.