Most efforts toward building kinase inhibitors have focused on the ATP binding pocket, but the ATP pocket is highly conserved amongst human kinases, causing sufficient selectivity to be difficult to achieve. Other binding pockets, however, are not present within all human kinase families, and thus represent potential targets for developing kinase inhibitors with greater selectivity. One such pocket is the hydrophobic binding pocket that becomes exposed when the kinase is in an inactive form, in which a conserved DFG motif in the N-terminus activation loop switches to a �DFG-out� conformation and obstructs the ATP site. We studied this�DFG-out� pocket using a computational hotspot detection algorithm, which identifies regions on the protein surface which disproportionately contribute to binding free energy upon ligand binding. When we applied our algorithm to cases with an existing ligand targeting the �DFG-out� pocket, we found that large hotspots were present in the location of ligand binding on the free structure of the corresponding kinase. Our results thus provide mechanistic insight into the mechanism of allosteric ligand design, and demonstrate the potential of the �DFG-out� binding pocket as a promising alternative to the ATP site for developing kinase inhibitors.

Analysis of the DFG-out binding pocket in kinases

248th National Meeting (2014)

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