Ray Crystallography

The goal of rational drug discovery and development is the enhancement of the activity of a ligand to obtain a clinically useful agent. The development of thera peutic entities from lead compounds requires the systematic modification of the chemical structure of the lead compounds to optimize the activity desired. One of the techniques that has been used in this process is x-ray crystallography. A knowledge of the three-dimensional structure of the pharmacologically relevant receptor-ligand complexes at the level of resolution achieved by using x-ray crystallography has the potential to speed the discovery and development of lead compounds into clinically effective drugs. Through these techniques, the specific interactions that are important in the molecular recognition and binding of the ligand to its macromolecular target can be ascertained. In addition, the development of the technology for obtaining large amounts of the target macromolecule, such as recombinant DNA technology and the technology for the analysis of the ligand-macromolecular interactions, has aided the rapid development of new chemical entities for clinical evaluation.

X-ray crystallography has been instrumental in the design of inhibitors active in the renin-angiotensin system (24) and in the design of lipophilic inhibitors of the enzyme thymidylate synthase (25). However, the development of inhibitors of human immunodeficiency virus (HIV) protease can be considered as one of the best examples of the extensive use of x-ray crystallography for the structure-assisted design of inhibitory molecules. The identification of the HIV protease as a member of the aspartate protease family facilitated the design of inhibitors of this enzyme, since earlier studies using x-ray crystallography had been carried out on aspartate proteases such as renin. Detailed reviews on the structure and function of HIV protease and its inhibitors have recently been published (26,27). Since the publication of the first crystallographic structure of an inhibitor com-plexed to the protease appeared, hundreds of structures of such complexes have been solved in dozens of laboratories. These studies have led to the clinical development and use of several protease inhibitors as therapy for HIV infection.

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