One of the major impediments in targeting the inhibition of kinases as therapeutic regimens concerns the associated potential side effects, and the identification of drug candidates with acceptable selectivity profiles remains a major challenge to discovery efforts in this area. Since the vast majority of drug candidates bind to the ATP binding pockets of kinases, we targeted this critical site as a basis for our phylogenetic analysis. Using available x-ray complex structures of representative kinases as a guide, residues which underlie the formation of the ATP binding pocket were mapped. Phylogenetic analysis and classification based on sequence regions corresponding to the ATP binding site was performed to afford classification of all kinase genes into major groupings (tree branches) in order to provide a representation of all kinases in this sequence space, and results so obtained will be compared to those derived from targeting the entire catalytic domain. Such information will be used as an aid to the selection of candidate genes for the construction of an "idealized" panel of kinases for selectivity profiling of compounds.
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