A Structural Perspective on Non-covalent Targeting of Conserved Polar Residues in Protein Kinases

Abstract All protein kinases contain conserved amino acid residues that bind the ATP substrate molecule and promote catalysis. As an intensely pursued drug target class, kinase inhibitor development is often streamlined by the utilization of three-dimensional structural data and binding modes to achieve a robust understanding of the molecular basis of kinase inhibition and inform structure-guided drug design. We analyze X-ray cocrystal structures of 300+ diverse kinase-inhibitor complexes and offer an assessment with respect to the targeting of conserved polar amino acid residues, which we term the “Catalytic Cluster Residues” (CCRs). These conserved Lys, Asp, and Glu residues can engage with the majority of kinase inhibitor types through non-covalent interactions. The orientations of these residues are coupled to the kinase conformational state, allowing for rational inhibitor design. Further perspectives on the utility of targeting the CCRs in the context of inhibitor potency, kinome selectivity, and drug development are presented.