Building Libraries with Chemical Diversity for Screening

我们与NIGMS资助的四个化学方法学和图书馆开发(CMLD)中的三个(波士顿大学、堪萨斯大学和匹兹堡大学)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，以扩大我们图书馆的广度。与传统药物化学小组的著名合作是与清华大学的刘刚教授和罗马大学的罗伯托·迪桑托教授。此外，我们还获得了一系列重点化合物，包括洛帕克、葛兰素史克Kline激酶文库、生物酚天然产物、ICCB已知生物活性物质，以及来自DCTD、NCI的一大系列合成化合物。作为美国国务院资助的一项减少威胁计划的一部分，哈萨克斯坦斯特普诺戈尔斯克前生物武器(BW)设施的科学家们被鼓励探索非BW科学视野。该项目是在哈萨克斯坦阿斯塔纳的国际科学技术中心(ISTC)的保护伞下进行的。MTP的工作人员曾五次前往哈萨克斯坦，以发展这一合作。我们组织了以哈萨克斯坦特有的800种植物为重点的植物收藏。到目前为止，我们已经收集了超过227个植物样本；植物提取物已经在NCI 60细胞筛选中进行了测试，并在MTP筛选中进行了预分离。我们还与哈萨克斯坦的病毒学和微生物学研究所合作，从高盐分和碱性土壤中筛选出300种极端嗜热放线菌提取物。另一个图书馆收藏了700种来自巴西塞拉多的植物提取物，作者是巴西利亚大学的埃斯平多拉博士。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。与伊斯坦布尔大学的合作以及在MTP中接待了几名土耳其科学家也收到了新的样本。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本。。我们最近开始将DTP的预馏分样品添加到我们的筛查集合中，取代了我们的内部集合。到目前为止，已经增加了32.6万个样本，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91,712个管子和1236个板材。在过去的12年里，MTP的化学多样性发展科开发了一个基于网络的定制化验和样品管理系统，使我们的研究人员能够管理样本库、设计化验试板以及存储和分析生物化验数据。该系统目前正在进行相当大的翻新，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. 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. 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. 326,000 samples have been added so far, with a similar number expected each year in the near future. Currently our storage system holds 91,712 tubes and 1236 plates. Over the past 12 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.