The potency of staurosporine against Lck derives in part from an induced movement of the glycine-rich loop of the enzyme upon binding of this ligand, which maximizes the van der Waals interactions present in the complex. In contrast, PP2 binds tightly and selectively to Lck and other Src family kinases by making additional contacts in a deep, hydrophobic pocket adjacent to the ATP-binding site; the amino acid composition of this pocket is unique to Src family kinases. The structures of these Lck complexes offer useful structural insights as they demonstrate that kinase selectivity can be achieved with small-molecule inhibitors that exploit subtle topological differences among protein kinases.

A symmetry analysis based upon the structure of simple molecules and their anticipated intermolecular interactions can lead to successful predictions of molecular packing and crystal symmetry. As a demonstration of these ideas an in-depth study of the oxalamide functionality as a persistent hydrogen bonding unit is presented. The synthesis and structural characterization of a series oxalamide dicarboxylic acids is presented and the structures compared with the analogous urea compounds. Both the urea and oxalamide dicarboxylic acids form designed two-dimensional hydrogen-bonded -networks with a significant degree of reliability. The urea designs are quite reliable when there is a molecular 2-fold axis, but competing hydrogen bond patterns are found when less symmetrical molecules are studied. The oxalamide design based on inversion centers is also quite reliable, with the designed layer structure found in most cases.

The protein kinase family represents both a huge opportunity and a challenge for drug development. The conservation of structural features within the ATP binding cleft initially led to the belief that specificity would be difficult to achieve. This dogma has now been clearly dispelled with the discovery and clinical testing of a group of first generation compounds, which are characterized by a high degree of selectivity towards a variety of oncology targets. The structural basis for selectivity and potency has now been clarified with the crystallization of a number of such targets in complex with inhibitors. The protein kinase inhibitor field is now ripe for the structure based exploitation of additional highly validated targets from a variety of therapeutic areas.

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