Tackling the Chemogenomic Space by Novel Screening Technologies

Abstract

Drug discovery in the chemogenomic space has seen some tremendous changes over the last decade. Compared to previous times, not only the number of available chemical compounds for screening, but also the number of molecular targets used for screening has increased significantly. This has triggered the need for very fast, efficient, and effective novel readout technologies for compound testing. Novartis has developed two novel high-throughput screening (HTS) technologies for that purpose — NanoScreen and SpeedScreen. NanoScreen is a highly miniaturized and fully automated HTS/uHTS test system with confocal single-molecule as well as non-confocal detection capabilities and is used for functional screening in the range of 1–5 µl per sample. The integration of the single-molecule readout technologies into the system enables highly sophisticated biochemical test systems with multi-parameter readout for very high data quality. SpeedScreen is a highly miniaturized and automated screening system for high-throughput affinity-selection of compounds. In practice, pools of compounds are incubated with the target protein and the unbound chemical compounds are removed from the target-compound complex via very fast, multiparallel size-exclusion-chromatography. The holoenzyme is disintegrated and analyzed via microbore reversed-phase high performance liquid chromatography (microbore RP-HPLC). Both systems have been developed and implemented with great success at the Novartis Lead Discovery Center (LDC) in Basel. These technologies have enabled us to access targets that would otherwise not have been possible, e.g., very expensive targets, “orphan” drug targets, or targets that are “non-tractable” by conventional screening technologies. Taken together, these novel screening technologies enable novel approaches for chemogenomic research that would have not been possible in the past.