Scaffold mining of kinase hinge binders in crystal structure database

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Drug Discovery

Background:

• Protein kinases are key drug targets, with most inhibitors targeting conserved hinge regions.
• Understanding kinase-inhibitor interactions is vital for developing effective therapeutics.

Purpose of the Study:

• To compile an inclusive list of hinge binding scaffolds from a large database of kinase-inhibitor complexes.
• To analyze the characteristics and diversity of these critical scaffolds for drug design.

Main Methods:

• Mining Pfizer's internal crystal structure database (CSDb) of X-ray binary complexes.
• Applying rule-based filtering to extract minimum ring scaffolds with specific functional groups.
• Annotating the ATP-binding site of human kinase complements.

Main Results:

• Identified approximately 600 unique hinge scaffolds from nearly 4,000 kinase-inhibitor complexes.
• Hinge scaffolds are predominantly flat, less lipophilic, and derived from a small set of common structures.
• Scaffolds exhibit varying degrees of kinase target specificity, with some being promiscuous.

Conclusions:

• A limited number of scaffolds form the basis for diverse kinase inhibitors.
• The compiled collection of hinge scaffolds can guide novel drug design and lead optimization.
• This resource supports strategies like hinge hopping for developing new kinase-targeted therapies.