Kinase hinge binding scaffolds and their hydrogen bond patterns.

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Drug Discovery

Background:

• Protein kinases are key intracellular signaling molecules and major drug targets.
• Kinase inhibitors often use small chemical scaffolds that form hydrogen bonds with kinase hinge residues.
• Hydrogen bonds to the kinase hinge are generally crucial for potent inhibition.

Purpose of the Study:

• To systematically analyze kinase inhibitor scaffolds and their hinge binding patterns.
• To understand the three-dimensional configurations of hinge hydrogen bonds.
• To identify common scaffold features and their impact on kinase interactions.

Main Methods:

• Systematic analysis of kinase scaffolds from the Pfizer crystal structure database (CSDb).
• Analysis of hinge hydrogen bond patterns from thousands of ligand-protein binary complexes.
• Focus on three-dimensional configurations of hydrogen bonds, including H6 NH, H4 CO, and H6 CO interactions.

Main Results:

• Diverse kinase inhibitors are derived from a small set of common scaffolds.
• Most inhibitors use H6 NH for hinge recognition; dual hydrogen bonds (H4 CO and/or H6 CO) are common.
• Triple hydrogen bonds are rare; an unusual non-canonical H5 conformation was observed.
• Additional hinge hydrogen bonds do not consistently increase potency and may decrease selectivity.

Conclusions:

• Understanding scaffold-hinge interactions is vital for kinase inhibitor design.
• Common scaffolds exhibit versatile binding capacities.
• The relationship between additional hydrogen bonds, potency, and selectivity requires careful consideration for successful therapy design.