Mass Spectrometry and Drug Discovery

Abstract

In the twenty‐first century, medicinal chemists are producing large numbers of organic compounds through a process called combinatorial chemistry and then testing them against pharmacological targets such as enzymes or receptors using high‐throughput screening. As a result, lead compounds can emerge from drug discovery programs in a few weeks instead of several years. Although a variety of spectroscopic and chromatographic techniques are used to support drug discovery, only HPLC or UHPLC combined with mass spectrometry (LC‐MS) are compatible with virtually all drug‐like molecules. In addition to providing a universal means to characterize drug molecules based on molecular mass 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 screen complex mixtures of compounds including 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 as well as screening applications such as frontal affinity chromatography‐mass spectrometry, gel permeation chromatography‐LC‐MS, affinity chromatography‐mass spectrometry, and pulsed ultrafiltration mass spectrometry. Since drug development issues such as metabolic stability and the formation of reactive metabolites are now being considered during the drug discovery process, some applications of mass spectrometry to early drug development are addressed.