Building Libraries with Chemical Diversity for Screening

我们与四个NIGMS资助的化学方法学和图书馆发展（CMLD）（波士顿大学，堪萨斯大学和匹兹堡大学）中的三个建立了MTA。仅这三个中心就提供了超过15，000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。MTP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的大量合成化合物。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。该计划是在哈萨克斯坦阿斯塔纳的国际科学技术中心（ISTC）的保护下进行的。MTP工作人员五次前往哈萨克斯坦发展这种合作。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227个植物标本;植物提取物已经在NCI 60细胞筛选中进行了测试，并在MTP筛选中进行了预分级。我们还与哈萨克斯坦的病毒学和微生物学研究所合作，从高盐和碱性土壤中筛选出300种嗜极端放线菌提取物。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，我们获得了大量韩国植物提取物。另一个图书馆是来自巴西塞拉多的700种植物提取物的集合，巴西利亚大学的Espindola博士。我们与这些实验室的持续合作也使我们能够获得大量纯化的植物天然产品。在与Blumberg研究所的合作中，我们从默克传统天然产品系列中获得了8，000种真菌提取物和25，000种细菌提取物。还收到了与伊斯坦布尔大学合作以及在中期计划中接待几名土耳其科学家的新样本。与哥本哈根穆勒实验室的一项新合作承诺将增加我们基于植物生物技术的样品。我们最近开始将DTP的预分级样本添加到我们的筛选集，取代我们的内部集。到目前为止，已经增加了15万个样本，预计在不久的将来每年都会增加类似的数量。目前，我们的存储系统可容纳246，085个试管和1454个平板。在过去的10年里，MTP的化学多样性开发部门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，设计分析板以及存储和分析生物测定数据。该系统目前正在进行大规模翻修，以改进其功能并增加新的能力。

We established MTAs with three of the four NIGMS-funded Chemical Methodologies & Library Developments (CMLD) (Boston University, University of Kansas, and University of Pittsburgh). These three centers alone have provided over 15,000 samples of known structure. Each CMLD has a distinct approach to library design, thus there is negligible overlap between their libraries. The MTP 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 Astana, Kazakhstan. MTP staff traveled to Kazakhstan on five occasions to develop this collaboration. We have organized plant collections focused on the 800 species endemic to Kazakhstan. To date, we have collected over 227 plant specimens; the plant extracts have been tested in the NCI 60 cell screen and prefractionated for testing in MTP screens. We have also collaborated with the Institute of Virology and Microbiology in Kazakhstan to screen 300 extracts of extremophilic actinomycetes from hypersaline and basic soils. 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. Another library is a collection of 700 plant extracts from the Brazilian cerrado, with Dr. Espindola of the University of Brasilia. Our ongoing collaboration with these laboratories has enabled us to receive a large collection of purified plant natural products as well. In a collaboration with the Blumberg Institute we have accessed 8,000 fungal extracts and 25,000 bacterial extracts from the Merck legacy natural products collection. New samples have also been received from a collaboration with the University of Istanbul, as well as hosting several Turkish scientists in the MTP. A new collaboration with the Moller lab in Copenhagen promises to add to our plant biotechnology based samples. We recently began to add prefractionated samples from the DTP to our screening set, replacing our in-house set. 150,000 samples have been added so far, with a similar number expected each year in the near future. Currently our storage system holds 246,085 tubes and 1454 plates. Over the past 10 years, the Chemical Diversity Development Section in the MTP 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. This system is currently under considerable renovation to improve its functionality and to add new capabilities.