Crystallography in Drug Design

Crystallography is traditionally one of the monitoring methods used in pharmaceutical industry. X-ray powder diffraction allows fast analysis of individual chemicals and their mixtures. Crystallography considers the habit of a given compound and its internal structure (crystalline, amorphous), and it gives a detailed description of polymorphism, molecular adducts, enantiomorphism, etc. Hazards of teratogenic activity of some drugs led to the inclusion of molecular structure, as determined by X-ray methods, into the list of standard characteristics demanded by the Drug Master Files. More recently, crystallography has also taken an active role in drug design. Atomic coordinates of thousands of bioactive molecules are now available from the Cambridge Structural Databank, Protein Data Bank and other files. This information is a good starting point for mechanistic drug design, especially if the structures of the effector and of the target are already known on the atomic level. However, structural information about the target molecule is frequently unavailable. In the case of enzyme-target, advantage can be taken of the fact that enzymes with similar functions often retain similar structural features and catalytic sites and may be modelled by using the structural information from a known enzyme. Receptor-target molecules represent a more difficult problem because they are larger and frequently membrane-associated. However, a knowledge of the effector structure is a good tool for mapping an active site of the receptor. Crystallography, in combination with other methods (NMR, IR, 3-D graphics, etc.) makes it possible to deal with such an ambitious problem in this field