ABSTRACT
The genome-sequencing projects have been tremendously successful in providing a
vast amount of protein sequence information for drug discovery efforts going forward. The fundamental challenge of the postgenomic era will be how to incorporate this deluge of protein sequence information into drug discovery strategies. Large-scale efforts to identify validated protein drug targets use cell-based methods, such as expression monitoring (1) as well as whole-organism genetic studies to identify essential genes or functions (2) for therapeutic intervention. These approaches will provide crucial biological validation, but it is not necessarily straightforward to match candidate lead compounds to target proteins based on this level of biological or functional annotation. Efficient lead discovery strategies will likely springboard from existing medicinal chemistry experience in designing small-molecule inhibitors or modulators of protein function. For rational and efficient lead optimization or even for virtual screening and computational docking strategies (3), knowledge of the physicochemical and structural features of the protein target are invaluable. That knowledge will be based on detailed information about target structure and the molecular function or functions encoded by that particular protein fold or structure.
