Protein kinases represent one of the largest protein families present in eukaryotes and mutated kinases are often observed in many different tumors. Kinase activity is tightly controlled by external signals and specific phosphorylation events are required to attain specific 3D conformational states that enhance the binding of the phosphate donor (ATP) in the active site. Certain driver mutations disrupt the kinase activity equilibrium by creating constitutively active conformations that do not depend on external signals for initiation, eventually leading the cell to disease states. Kinases, in spite of their overall sequence and bi-lobe structural similarity, need specific active site residues for activity. In this study, we aimed to develop a structure-focused in silico approach to provide guidelines in designing suitable inhibitors for family-specific inhibitors. We present here the results of receptor-focused in-silico docking of nine marketed drugs to 19 different wild-type and mutated kinases chosen from a wide range of families. Our results show that by using the appropriate structure models and pathway analysis one can identify family-specific inhibitors. Type II drugs display high selectivity for DFG-out kinase conformations. On the other hand Type I drugs are less selective and show binding preferences for both the open and closed forms of selected kinases. Using this receptor-focused approach, we also capture the observed fold change in binding affinities between the wild-type and disease-centric mutations.

Structure-focused modeling approach to identify family-specific kinase inhibitors

249th National Meeting (2015)

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