Screening Platform at the Rudolf-Boehm-Institute

Defining novel chemical tools and pharmacological lead compounds

Background Libraries Services Equipment Downloads

Background: Recent proceedings in scalable state-of-the-art analytical methodology in life sciences are increasingly enabling scientists to define potential pharmacological targets and to identify novel targets of known drugs or bioactive natural products. During the last 10 years, this still ongoing process has led to a renaissance of academic drug development activities. Although screening activities can be highly effective in developing cell-biological tools to address open questions in basic science and in identifying lead compounds that may become a starting point for drug development activities, the high costs of hosting and distributing chemical libraries remained a strong limiter of such activities. Nonetheless, the development and scientific use of novel chemical modulators is increasingly applied for solving biological problems and has formed a novel interdisciplinary field of research, which has been coined “Chemical Biology”.

Libraries: To date, the improved design of chemical compound libraries, including scoring for drug-likeliness and intelligent addressing of a maximally diverse chemical space with reasonable compound numbers, has proven successful in reducing screening costs and times while maintaining a high probability of obtaining valuable hits. Of about 8.6 million commercially available compounds, the ChemBioNet collection, which has been designed by Ronald Kühne at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin, encompasses 16,771 compounds that are highly enriched for typical pharmacophore basic structures that are extracted from the World Drug Index (WDI), arranged in novel combinations to achieve maximal diversity, and selected for low overlap of compound shapes and surface charge distribution. Complementary to the ChemBioNet collection, the Spectrum Collection comprises approved small molecule drugs that have recieved FDA admission or have reached phase III level of clinical trials. Furthermore, the Spectrum Collection contains 800 natural compounds with annotated biological activity, frequently used cell biological tools and blockers, as well as 160 toxins. The spectrum Collection offers the possibility to unravel novel actions of known drugs and modulators. It is, thus, the library of choice to proceed quickly into novel experimental therapeutic directions with already approved drugs. Moreover, history has clearly demonstrated that "old drugs" are still a very effective source and starting point for drug development programs. The LOPAC1280 compound collection represents a wide array of cellular signalling tools, including agonists or antagonists towards several receptor classes, ion channel, kinase or enzyme blockers and other tools that interfere with specific key principles in cellular signal transduction. Thus, screening the LOPAC1280 library may provide new insight into signalling and signalling cross-talks in molecularly defined pathways or on cellular responses that are still poorly understood. back

Our Services: As part of the ChemBioNet, the RBI now hosts and distributes three libraries: the Spectrum Collection, the LOPAC1280 collection from Sigma-Aldrich, and the chemically diverse ChemBioNet library. Libraries are provided and diluted into the desired measuring solutions preferrably in 384-well format at final concentrations of 10-20 µM. Plate reader or fluorescence imaging plate reader capacities of the RBI can be shared for collaborative screening projects. Most compounds that are present in the libraries can be commercially repurchased for further characterisation. Further support includes hit clustering, cherry picking and the design of focussed libraries that test the structure-activity relationship and are expected to help optimising the binding affinity and target selectivity. Ideally, screening activities will result in the establishment of a cell biological tool that can be used for basic science and to intellectual property that may become a starting point for translational activities. Typical procedures that characterize an academic drug development initiative are visualized in a schematic drawing. Interested scientists are asked to contact Prof. Michael Schaefer. back

Equipment: - ChemBioNet Library (16,671 compounds) - Spectrum Collection (2,000 compounds) - Liquid handling robotics (Tecan Freedom EVO) - Multi-format and multi-detection plate reader (BMG POLARstar Omega) - Fluorescence plate imager with manual pipetting platform - Heat sealer back

Downloads: Compound listings and plate organisation scheme - Spectrum Collection: compound listings and plate organisation for 384-well plates (MS Excel file) - LOPAC1280: compound listings and plate organisation for 384-well plates (MS Excel file) - ChemBioNet compound library: compound listings and plate organisation no structures (MS Excel file) - ChemBioNet compound library: compound structures, IDs and properties (zipped SDF-file) back