Modern drug discovery is a highly integrated process that contains various interactive and interdependent components. Mass spectrometry plays an important role in every step of this process. Several other chapters of this book illustrate the application of mass spectrometry in drug discovery, such as target identification and validation (genomics, proteomics, and metabonomics), high throughput screening (HTS), and drug metabolism and pharmacokinetics (DMPK). In this chapter, we discuss the application of mass spectrometry in the generation of compound libraries for HTS and for lead optimization, and in the analysis and management of these compound libraries.
In a small-molecule-based drug-discovery process, the creation of large numbers of well-designed compounds is a critical step to ensure the success of drug lead discovery and optimization. Combinatorial chemistry or its more common form, high throughput parallel organic synthesis (HTOS), is often used to generate these compound libraries [1-4]. Mass spectrometry is used throughout the compound generation process from design and optimization of libraries, to synthesis monitoring, and finally, to high throughput purification (HTP) and characterization of the library compounds. In addition,
Integrated Strategies for Drug Discovery Using Mass Spectrometry, Edited by Mike S. Lee © 2005 John Wiley & Sons, Ltd.
the high throughput, high sensitivity, and structural information provided by mass spectrometry facilitate profiling of physiochmical and pharmaceutical properties of the library compounds. Finally, as pharmaceutical companies increasingly rely on HTS for lead discovery, the establishment and maintenance of a high-quality repository compound collection have become an important issue. Mass spectrometry has been used in the study of quality and stability of the repository compound collection.
Small-molecule libraries synthesized in the parallel format may be those directed toward either lead discovery or lead optimization, and may be synthesized either on a solid-support or in solution. The large numbers of discrete compounds generated by these parallel formats require analysis, and most frequently, purification. This chapter will illustrate how mass spectrometry assists these efforts.
With the success of combinatorial chemistry and HTS, more and more new structural entities are created or acquired and lead compounds discovered. As a consequence, there is an increased demand for high throughput measurement of the quality, physiochemical, and pharmaceutical properties of absorption, distribution, metabolism, and excretion (ADME) of these compounds. This increased demand has created opportunities for the application of mass spectrometry to these research activities.
Finally, the maintenance and efficient management of the increased number of compounds in the chemical repository of drug-discovery operations pose new challenges. The need for the investigation of large numbers of compounds with diverse properties and the various conditions and formats for compound storage and handling require improved analytical methods. Mass spectrometry has been the workhorse in these investigations.
The various analyses and measurements of the large numbers of organic compounds just described have several common requirements: (1) high throughput, (2) general applicability to compounds of diverse structures and properties, (3) selectivity and often separation of complex components, and (4) identification as well as quantitative analysis. Mass spectrometry, especially in combination with high-performance liquid chromatography (HPLC), is ideally suited for such applications. A number of reviews on the application of mass spectrometry to compound library synthesis and analysis have been published [5-20]. Good reviews on HPLC as well as specific equipment such as columns and detectors are also available [21,22].
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