Building Libraries with Chemical Diversity for Screening

点击翻译按钮获取中文摘要

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.