(A) De-wetting propensities of C-Kit residues in contact with imatinib (PDB.1T46; green bars) and of aligned residues in Bcr-Abl kinase (PDB.1FPU; red bars) and Lck (PDB.3LCK; black bars). Residue i is in contact with the ligand if an atom of the latter lies within its domain, D(i) (see Methods). The de-wetting propensity is quantified by the mean residence time of solvating water molecules. Error bars denote Gaussian dispersion over 5 molecular dynamics runs. (B) Pattern of de-wetting hot spots that arise as backbone hydrogen-bonded residues in C-Kit kinase (ribbon backbone representation in light blue; de-wetting hot spots in green), aligned with Bcr-Abl kinase (magenta backbone; de-wetting hot spots in red). The imatinib methylation site leading to the expulsion of water from C-Kit C673-G676 de-wetting hot spot is highlighted (yellow rectangle). Imatinib is thus modified to favorably expel interfacial water molecules from the C-Kit microenvironment, a feature not conserved in Bcr-Abl. Hydrogen bonds are represented as segments joining α-carbons of the paired residues, and those lacking the propensity for dehydration are shown as light gray segments. Residues from the C-Kit chain are labeled in green, and those from Bcr-Abl are labeled in white. (C) Differences in de-wetting hot spots upon alignment of C-Kit (light blue backbone; hot spots in green) and Lck kinase (gold backbone; hot spots in black). Labels for Lck residues are shown in white. (D) Prototype molecule WBZ_4 (N-{5-[4-(4-methyl piperazine methyl)-benzoylamido]-2-methylphenyl}-4-[3-(4-methyl)-pyridyl]-2-pyrimidine amine). The added methyl group is indicated in red.