The NIH Roadmap for Medical Research( recognizes the importance of molecular library screening for identifying and revealing to the public new collections of bioactive compounds. As part of their initiative, in 2007, our campus established the NIH funded UCSC Chemical Screening Center, which enables high throughput screening (HTS) using a series of contemporary instruments. Among these are a Matrix WellMate liquid dispenser robot for preparation of multi-well plates (96 or 384), a Perkin Elmer Janus MDT robotic pipettor and pin transfer station, for accurate and automated delivery of compounds, and a Perkin Elmer Envision plate reader for absorption and fluorescence assays. A Molecular Devices ImageXpress automated microscope for high content screening It has a Nikon objectives, up to 60x, with bright fiber optic light source, robotic stage that accommodates multi-well plates and slides, and image analysis software. The Perkin Elmer Verispan is an X-Y-Z robotic liquid handler with an independently controllable 8-tip pipet, used for performing serial dilutions, compound cherry picking, and any other routine automated liquid handling task. These instruments enable the most rapid and sensitive approach available for identifying new compounds.
The Chemical Screening Center also has available a wide range of compounds. Screens begin with the commercially available Spectrum collection of 2000 known drugs and bioactives and then proceeds to the ChemDiv library, which contains approximately 1,700 different molecular scaffolds, with an average of 9 structural analogs within each scaffold type (Figure 1). The approximately 50,000 ChemDiv compounds are all drug-like with low molecular weight, low polar surface area and appropriate numbers of hydrogen bond donors and acceptors. We anticipate that the wide functional group availability within this library will provide a wealth of information. In addition to ChemDiv, we also have a collection of over 3,000 compounds from the National Cancer Institute.
A distinguishing and absolutely unique feature of the UCSC Chemical Screening Center is the broad library of terrestrial and marine natural products (Figure 1). UCSC researchers and their collaborators have collected over 20,000 potential compounds, many of which have been recently isolated. Many of these compounds are not yet characterized, but instead are stored in “peak libraries” where each HPLC fraction peak represents a discrete chemical entity. As HTS hits emerge, they are then characterized using high-resolution mass spectrometry, NMR and crystallography, as appropriate.
Figure 1. Example chemical structures available in the UCSC Screening Center. These were chosen based on their aromatic rings, which may serve as recognition elements. The top row shows a ChemDiv scaffold and various functional groups. The bottom row shows two recent marine natural products from the cyanobacterial Symploca and the sponge Latrunculia, respectively, that are representative scaffolds available in its respective fractionated peak library.