Amzoiu Manuel-Ovidiu, Popescu Georgeta Sofia, Amzoiu Emilia, Ciocîlteu Maria Viorica, Manda Costel Valentin, Rau Gabriela, Gresita Andrei, Taisescu Oana
Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania.
Faculty of Food Eng, University of Life Science "King Michael" from Timisoara, 300645 Timisoara, Romania.
Life (Basel). 2025 Aug 6;15(8):1247. doi: 10.3390/life15081247.
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.
咖啡因是一种广泛消费的精神活性化合物，已知它通过与细胞色素P450 3A4（CYP3A4）等关键酶相互作用来影响药物代谢和疗效。本研究使用分子对接模拟研究了咖啡因对伊马替尼（一种一线BCR-ABL酪氨酸激酶抑制剂）结合行为的分子影响。使用HyperChem进行结构优化和亲脂性分析，同时使用HEX软件（版本8.0.0）针对CYP3A4受体（PDB ID：1W0E）进行对接。评估了两种给药方案：同时形成咖啡因 - 伊马替尼复合物以及先将咖啡因预结合到CYP3A4上再进行顺序给药。与单独的伊马替尼（logP = -1.29）相比，咖啡因 - 伊马替尼复合物的亲脂性预计增加（logP = 3.09），这可能表明其膜通透性和组织分布增强的潜力。对接模拟显示，与单个化合物相比，该复合物与CYP3A4的结合亲和力更强（-350.53 kcal/mol），并且当CYP3A4与咖啡因预复合时，伊马替尼的结合有所改善（-294.14 kcal/mol对-288.19 kcal/mol）。前沿分子轨道分析表明复合物的反应性增加（ΔE = 7.74 eV），支持了药效学行为改变的假设。这些发现表明，咖啡因可能通过增强受体结合和改变药物分布来调节伊马替尼的代谢谱和治疗效果。该研究强调了在药物开发和治疗规划过程中评估饮食成分的重要性，特别是对于由CYP3A4代谢的药物。
