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Fluorescence Polarization Screening Assays for Small Molecule Allosteric Modulators of ABL Kinase Function

Fig 10

Molecular dynamics (MD) and molecular docking predict binding of compound 142 to the ABL SH3:linker interface.

Top: The lowest energy pose of the ligand (compound 142; carbon atoms rendered in green) is shown docked to a snapshot of an MD simulation of the ABL N32L structure. SH3 domain residues predicted to contribute to ligand binding include Asn97, Thr98, Asn115, Trp118, and Trp129 (carbons in red). The backbone of the linker is shown as an orange ribbon, with Gly246, Val247, Pro249 and Trp254 predicted to contribute to the binding pocket. One of the piperidine groups of compound 142 makes hydrophobic contacts with linker Pro249 and Trp254, while the pyrimido-pyrimidine scaffold of compound 142 is π-stacking with Trp118. Middle panel: Model of the SH3:linker interface in the N32L region based on the crystal structure of the downregulated ABL core (PDB:2FO0), highlighting the interaction of linker Pro249 with SH3 Trp118 and Trp129. Ligand binding (top panel) is predicted to displace this regulatory interaction, leading to kinase activation. Lower panel: The lowest energy pose of compound 142 is shown docked to a snapshot of an MD simulation of the SH3 domain in the absence of the linker. The position of the 142 ligand is similar (within 1.5 Å RMSD) to that in the SH3 domain of N32L (top), except that the ligand contacts Glu117 rather than linker residues Gly246 and Val247. Without the linker, the potential hydrophobic stabilization of the 142 piperidine group is also lost.

Fig 10