Modulatory Effects of Caffeine on Imatinib Binding: A Molecular Docking Study Targeting CYP3A4

Caffeine is a widely consumed psychoactive compound known to influence drug metabolism and efficacy through interactions with key enzymes such as cytochrome P450 3A4 (CYP3A4). This study investigates the molecular impact of caffeine on the binding behavior of imatinib, a first-line BCR-ABL tyrosine kinase inhibitor, using molecular docking simulations. Structural optimization and lipophilicity analyses were conducted using HyperChem, while docking was performed with HEX software (Version 8.0.0) against the CYP3A4 receptor (PDB ID: 1W0E). Two administration scenarios were evaluated: concurrent caffeine-imatinib complex formation and sequential administration with caffeine pre-bound to CYP3A4. The caffeine-imatinib complex exhibited a predicted increase in lipophilicity (logP = 3.09) compared to imatinib alone (logP = -1.29), which may indicate the potential for enhanced membrane permeability and tissue distribution. Docking simulations revealed stronger binding affinity of the complex to CYP3A4 (-350.53 kcal/mol) compared to individual compounds, and improved imatinib binding when CYP3A4 was pre-complexed with caffeine (-294.14 kcal/mol vs. -288.19 kcal/mol). Frontier molecular orbital analysis indicated increased reactivity of the complex (ΔE = 7.74 eV), supporting the hypothesis of altered pharmacodynamic behavior. These findings suggest that caffeine may modulate imatinib's metabolic profile and therapeutic efficacy by enhancing receptor binding and altering drug distribution. The study underscores the importance of evaluating dietary components during drug development and therapeutic planning, particularly for agents metabolized by CYP3A4.