Protein crystallography in drug discovery

Drug discovery has traditionally relied either on serendipitous observations (a classic example would be Sir Alexander Fleming’s discovery of the antibacterial properties of penicillin1 ), or on screening of natural and synthetic compounds in combination with medicinal chemistry (see 1.07 Overview of Sources of New Drugs; 3.32 High-Throughput and High-Content Screening). While remaining indispensable to the drug discovery process, the conventional methods are beginning to give way to more rational approaches that utilize available knowledge on the three-dimensional (3D) structure of a drug target (see 4.24 Structure-Based Drug Design – The Use of Protein Structure in Drug Discovery).2 This information can be generated experimentally by employing biophysical methods such as x-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy, or theoretically by utilizing experimentally derived 3D structures of related macromolecules to generate 3D homology models of the drug target (see 3.21 Protein Crystallography; 3.22 BioNuclear Magnetic Resonance; 4.10 Comparative Modeling of Drug Target Proteins).3