Structure- and Similarity-Based Survey of Allosteric Kinase Inhibitors, Activators, and Closely Related Compounds

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Allosteric kinase inhibitors are recognized for their high selectivity, making them promising candidates for kinase drug discovery.
• Understanding allosteric mechanisms is crucial for both basic research and rational drug design.
• While identifying allosteric kinase inhibitors is challenging, numerous X-ray structures of kinase complexes with these inhibitors are available.

Purpose of the Study:

• To conduct a comprehensive survey of allosteric kinase inhibitors and activators using publicly available X-ray structures.
• To map the binding sites and analyze the distribution of these allosteric modulators within kinase binding pockets.
• To provide a detailed, structure-based perspective on allosteric kinase inhibition.

Main Methods:

• Systematic collection and analysis of publicly available X-ray crystallographic structures of kinases.
• Mapping of allosteric inhibitor and activator binding sites within the kinase structures.
• Identification and analysis of structural features, active analogues, and target annotations.

Main Results:

• Cataloged a significant number of allosteric kinase inhibitors and activators based on structural data.
• Mapped diverse binding sites and characterized the distribution of allosteric modulators across different kinase pockets.
• Identified structural analogues and high-confidence target annotations, revealing potential off-target activities for some inhibitors.

Conclusions:

• Structural data is key for confirming and characterizing allosteric kinase inhibitors.
• This structure-based survey provides valuable insights into the landscape of allosteric kinase inhibition.
• The findings highlight the potential for designing more selective kinase inhibitors and understanding their complex activities.