C─H⋯O hydrogen bonds in kinase-inhibitor interfaces

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• C─H⋯O hydrogen bonds are weak but significant interactions, found in biological systems like nucleic acids and proteins.
• These bonds play a role in stabilizing protein secondary structures and in protein-ligand interactions.
• The hinge region of protein kinases is a known interaction site for inhibitors via canonical hydrogen bonds.

Purpose of the Study:

• To investigate the role of C─H^inhibitor ⋯O^protein hydrogen bonds in complexes of FDA-approved kinase inhibitors with their target kinases.
• To assess the prevalence and significance of these interactions in drug-target binding.

Main Methods:

• Analysis of crystal structures of protein kinase inhibitor-kinase complexes from the Protein Data Bank.
• Identification and characterization of C─H⋯O hydrogen bonds between inhibitors and kinase hinge regions.

Main Results:

• C─H⋯O hydrogen bonds are frequently observed between kinase hinge regions and FDA-approved inhibitors.
• In most analyzed complexes, hinge carbonyl groups accept hydrogen bonds from inhibitor C─H groups (aromatic or adjacent to electronegative groups).
• These interactions occur alongside canonical hydrogen bonds involving the hinge backbone.

Conclusions:

• C─H⋯O hydrogen bonds contribute significantly to the binding of kinase inhibitors to the conserved hinge motif.
• These findings offer valuable insights for the rational design of novel kinase inhibitors with improved binding affinity and therapeutic efficacy.