Introduction

Progress made in the areas of molecular biology, combinatorial chemistry and laboratory automation during the past few decades has transformed the process of drug discovery. Whilst the sequencing of the human genome has fuelled our imagination on the availability of novel drug targets, combinatorial and parallel chemistry technologies have rendered large libraries available to drug companies which can be screened efficiently only by using sophisticated and reliable laboratory automation. A plethora of detection technologies has been developed which allows for the rapid screening of compounds on both small and economical scales. Hence, during the 1990s, as dedicated units became established within pharmaceutical companies, the discipline of high-throughput screening (HTS) was born.

The processes and technological developments in the area of cellular screening form the focus of this chapter. Cellular assays provide some clear technical advantages, for example when the isolation of a biochemical target is difficult or cannot be up-scaled, as is often found with membrane proteins. In addition, there are conceptual advantages when certain targets, for example nuclear receptors, undergo complex intracellular interactions which cannot be adequately reproduced in a simple biochemical set-up. It must be emphasized however that, as has been discussed widely in earlier debates in the field, biochemical and cellular screening approaches still have their intrinsic "pros" and "cons" [1, 2]. Although the natural environment of the cell will present the biochemical targets under biologically relevant conditions, the cellular screening of intracellular targets bears the disadvantage that penetration of the cellular membrane might distort the chemical structure-activity relationship and thus render the series analysis of hits and chemical lead optimization difficult. On the other hand, screening directly for compounds that already are known to have relevant cellular activity might simplify the hit selection process and shorten lead optimization cycles.

128 | 5 Drug Screening Using Cell Lines: Cell Supply, High-Throughput and High-Content Assays 5.2

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