Hydrophobic and polar interactions of FDA-approved small molecule protein kinase inhibitors with their target enzymes

Abstract

Dysregulation and mutations of protein kinases play causal roles in many diseases including cancer. The KLIFS (kinase–ligand interaction fingerprint and structure) catalog includes 85 ligand binding-site residues occurring in both the small and large protein kinase lobes. Except for allosteric inhibitors, all FDA-approved drug-target enzyme complexes display hydrophobic interactions involving catalytic spine residue-6 (KLIFS-77), catalytic spine residue-7 (KLIFS-11), and catalytic spine residue-8 (KLIFS-15) within the small lobe and residues within the hinge-linker region (KLIFS-46–52). Except for allosteric antagonists, the approved drugs form hydrogen bonds with the third hinge residue (KLIFS-48) of their target. Most of the approved drugs, including the allosteric inhibitors, interact with the small lobe gatekeeper residue (KLIFS-45). The type IIA inhibitors have the most hydrophobic interactions with their target enzymes. These include interactions with KLIFS-27/31/35/61/66 residues of the back pocket within both the small and large lobes. There is also interaction with KLIFS-68 (regulatory spine residue-1), the conserved histidine of the catalytic loop that is found in the back pocket of type II antagonists, but within the front pocket of the other types of inhibitors. Owing to the participation of protein kinase signaling cascades in a wide variety of physiological and pathological processes, one can foresee the increasing use of targeted inhibitors both as primary and secondary treatments for many illnesses. Further studies of protein kinase signal transduction pathways promise to yield new and actionable information that will serve as a basis for fundamental and applied biomedical breakthroughs.