Introduction

In the reductionist approach to drug discovery, where a disease state is approached through target-driven ligand development, mass spectrometry (MS) does not yet play a prominent role. It has a comfortable home in target characterization and preclinical studies of lead compounds - upstream and downstream of the initial discovery phase - but is rarely considered a tool for the initial discovery phase. Impressive engines of lead discovery have been developed based on optical technologies, with large appetites for compound archives and combinatorial library products. Drug discovery assays involving mass spectrometry face stiff competition with these high-volume, wellplate assays. But MS-based systems need not be wielded in a competitive manner. The advantage to mass spectrometry lies in its ability to characterize compounds in mixtures with high sensitivity and only moderate requirements for sample purification. Thus, when MS is considered as a detector for drug discovery applications, it is appropriate to leave the high-volume, single-compound analyses to the array technologies currently implemented in screening laboratories. If MS is to play a significant role in lead discovery, it will be to extend access to chemical diversity, for example in screening less well defined mixtures of potential ligands such as natural product extracts. Frontal affinity chromatography-mass spectrometry (FAC-MS) is an analytical concept that offers a generalized approach to compound screening via MS, and while it can be utilized as an assay for single compounds, it is well adapted to deriving compound-specific binding data from complicated mixtures that would confound plate-based bioassays. In this chapter we will present the fundamentals of the FAC-MS technique and describe system advancements and recent applications, which together suggest a strong role for the technique in lead discovery.

D 9 12 1fl

Time [min]

Fig. 6.1 A breakthrough curve generated by the frontal analysis method [31]. The analysis represents a high-volume injection of caffeine through a reversed-phase column, at a concentration representative of the linear region of the binding isotherm. Adapted with permission from Elsevier.

D 9 12 1fl

Time [min]

Fig. 6.1 A breakthrough curve generated by the frontal analysis method [31]. The analysis represents a high-volume injection of caffeine through a reversed-phase column, at a concentration representative of the linear region of the binding isotherm. Adapted with permission from Elsevier.

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