Lead compounds, small molecule drug screening

Currently, this is a major application of protein crystallography in most of the major drug companies. One of the best examples of this approach is the design of inhibitors for HIV protease (Dash et al., 2003). In brief, once the 3-D structure of HIV protease was determined, the active site was identified and used to screen small molecule libraries for potential compounds that could bind to HIV protease. These compounds were then tested for their ability to inhibit the protease. Lead compounds were then used to iteratively improve the inhibitors, using crystallographic studies, computational modeling, and biochemical tests. 

Characterisation of the structure and conformation of small biologically active molecules is part of the standard approach to lead generation in drug design studies. In particular, it is now possible to automatically synthesise many thousands of small molecules and then rapidly measure their effects in a given pharmacological test system. The power of such techniques comes from the immense number of compounds which can be generated and screened for activity. Two studies have evaluated HPLC-NMR in the field, one based on a mixture of 27 closely related tripeptides [24] and the other on two separate mixtures of four aromatic compounds and three pentapeptides [25]. 

Bevan P, Ryder H, Shaw I (1995) Identifying small-molecule lead compounds the screening approach to drug discovery. Trends Biotechnol 13 115-121... 

---