Macromolecular crystallography as a tool for investigating drug, enzyme and receptor interactions

1. Protein crystallography is an essential tool for the discovery and inves tigation of pharmacological interactions at the molecular level. It allows investigators to directly visualize the three-dimensional structures of pro teins, including enzymes, receptors and hormones. 2. Increasingly, knowledge of these interactions is being used in the drug- discovery process. This is popularly called structure-based drug design. Th e desired drug could be an enzyme inhibitor or an agonist that mimics endog enous transmitters or hormones. 3. Once the 3-D structure of a pharmacologically relevant target is known, computational processes can be used to search databases of compounds to ide ntify ones that may interact strongly with the target. Lead compounds can b e improved using the 3-D structure of the complex of the lead compound and its biological target. 4, The present review describes the processes involved in the determination of a structure by means of protein crystallography and the use of structur es in the drug-discovery process. A number of successful examples of struct ure-based drug design are described. The limitations of the techniques are discussed.