Sunitinib: from charge-density studies to interaction with proteins

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Protein kinases are crucial drug targets for numerous diseases.
• Sunitinib malate, a type I tyrosine kinase inhibitor, gained drug approval in 2006.
• Understanding drug-target interactions at a molecular level is vital for drug development.

Purpose of the Study:

• To conduct a comprehensive analysis of sunitinib malate's crystal structure.
• To investigate the structural complexes of sunitinib with various protein kinases.
• To elucidate the charge-density distribution and intermolecular interactions of sunitinib in its crystalline form and in complex with kinases.

Main Methods:

• High-resolution single-crystal X-ray diffraction measurements.
• Aspherical atom crystallographic databases for charge density reconstruction.
• Hirshfeld surface analysis and topological studies of intermolecular interactions.

Main Results:

• The crystal structure of sunitinib malate reveals interaction patterns similar to those in protein kinase binding pockets.
• Sunitinib forms nine conserved bond paths, including hydrogen bonds and C-H···O/π contacts, with kinases like VEGRF2, CDK2, G2, KIT, and IT.
• Sunitinib demonstrates consistent electrostatic interaction energy with studied proteins and adapts its conformation to optimize binding, particularly hydrogen bonds.

Conclusions:

• Sunitinib's binding interactions within protein kinase pockets are conserved between its crystal structure and drug-target complexes.
• The drug's conformational flexibility allows it to enhance electrostatic interactions, such as hydrogen bonds, within kinase binding sites.
• These adaptable binding characteristics likely contribute to sunitinib's broad-spectrum activity as a kinase inhibitor.