Inhibitors to the Src SH2 Domain: A Lesson in Structure–Thermodynamic Correlation in Drug Design

Src homology 2 (SH2) domains play a key role in many tyrosine kinase-mediated intracellular signal transduction pathways. Aberrancies in the interaction of these domains can lead to a range of disease states. As a result, the pharmaceutical industry has made a large temporal and financial investment in the development of specific inhibitors to these domains. Focusing on the interactions of the SH2 domain from the protein Src, we report how the correlation of structural and thermodynamic data allows an assessment of the process of drug design. The binding site of the protein includes two pockets; one interacts with phosphotyrosine groups on cognate ligands, and the other accommodates an aliphatic hydrophobic side chain. The interaction with cognate ligands is also mediated by a network of water molecules. Thermodynamic data from isothermal titration calorimetric studies suggest that modification of the interactions in the SH2 binding site has been largely unsuccessful in producing high-affinity inhibitors. Furthermore, it appears that compounds that disrupt the interfacial water pay the price for the loss of the contribution to the free energy from a network of hydrogen bonds.