Mass Spectrometry and Drug Discovery

AbstractCombinatorial chemistry and high‐throughput screening have become the primary tools of the medicinal chemist in an effort to accelerate the pace of drug discovery. The goal of this new paradigm is to produce in a short time large numbers of synthetic organic compounds representing a great diversity of chemical structures through a process called combinatorial chemistry, and then quickly screen themin vitroagainst pharmacologically significant targets such as enzymes or receptors. As a result, lead compounds might emerge from such combinatorial chemistry drug discovery programs in a few weeks instead of several years. Although a variety of spectroscopic and chromatographic techniques are being used to support drug discovery in various capacities, only high performance liquid chromotography (HPLC) combined with mass spectrometry (LC‐MS and LC‐MS‐MS) is compatible with virtually all drug‐like molecules. In addition to providing a universal means to characterize and distinguish drugs and drug candidates based on both molecular weight and structural features, mass spectrometry provides high throughput. With the development of routine LC‐MS interfaces and ionization techniques such as electrospray and atmospheric pressure chemical ionization, mass spectrometry has also become an ideal HPLC detector for the analysis of combinatorial libraries. Furthermore, a variety of mass spectrometry–based screening assays have been developed to address the need to screen complex mixtures of combinatorial compounds as well as to screen natural product extracts as a means of expanding the molecular diversity of drug leads. The use of mass spectrometry in support of combinatorial library synthesis and purification is addressed in this chapter, as well as screening applications such as frontal affinity chromatography–mass spectrometry, gel permeation chromatography–LC–MS, Fourier transform ion cyclotron resonance (FTICR) electrospray mass spectrometry of receptor–ligand complexes, affinity chromatography–mass spectrometry, and pulsed ultrafiltration mass spectrometry.