Chuang Sara, Velkov Tony, Horne James, Wielens Jerome, Chalmers David K, Porter Christopher J H, Scanlon Martin J
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
J Med Chem. 2009 Sep 10;52(17):5344-55. doi: 10.1021/jm801349e.
Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
肝脂肪酸结合蛋白（L-FABP）在肠细胞中含量很高，参与脂肪酸的胞质溶解。此外，L-FABP已被证明能结合内源性和外源性亲脂性化合物，这表明它可能在调节这些化合物在肠细胞内的吸收和分布中也发挥作用。此前，我们已经描述了L-FABP与一系列药物的结合，包括一系列贝特类药物。在本研究中，我们构建了L-FABP-贝特类药物复合物的结构模型，并对含有羧酸或酯官能团的贝特类药物的结合进行了热力学分析。对当前数据的分析表明，与不含羧酸盐的贝特类药物相比，含羧酸盐的贝特类药物的结合位置和能量都有所不同。因此，本研究中呈现的数据提示了一些潜在机制，这些机制是贝特类药物与L-FABP之间分子识别和决定特异性相互作用的基础。
