Intermolecular Interactions in Crystal Structures of Imatinib-Containing Compounds

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Imatinib is a key therapeutic agent for leukemia, functioning as a tyrosine kinase inhibitor.
• The imatinib molecule exhibits flexibility, participating in hydrogen bonding and hydrophobic interactions.

Purpose of the Study:

• To investigate the molecular conformations of imatinib.
• To analyze the role of intermolecular interactions in stabilizing these conformations.

Main Methods:

• Density functional theory (DFT) calculations for rotation potentials along single bonds.
• Analysis of crystal structures from the Cambridge Structural Database and Protein Data Bank.

Main Results:

• Rotation around the N-C amide bond leads to two stable conformations: extended and folded.
• Experimentally observed hydrogen bonds align with predicted likelihoods.
• Ligand-receptor complexes show more hydrogen bonds than imatinib salts due to kinase binding pockets.
• Hydrophilic interactions are similar for both conformations; pi-stacking favors the folded form.

Conclusions:

• Molecular flexibility and specific intermolecular interactions dictate imatinib's conformations.
• Understanding these conformations is vital for optimizing imatinib's therapeutic activity.