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Abstract：
Thiazolidinedione derivatives (TZDs) have attracted attention because of their pharmacological effects. For example, certain TZDs have been reported to ameliorate type II diabetes by binding and activating PPARs (peroxisome proliferator-activated receptors). Nonetheless, no information is available on the interaction between the heterocyclic 2, 4-thiazolidinedione (2,4-TZD) moiety and serum albumin, which could affect the pharmacokinetics and pharmacodynamics of TZDs. In this study, we investigated the binding of 2,4-TZD to human serum albumin (HSA). Intrinsic fluorescence spectroscopy revealed a 1:1 binding stoichiometry between 2,4-TZD and HSA with a binding constant (Kb) of 1.69 ± 0.15 × 103 M-1 at 298 K. Isothermal titration calorimetry studies showed that 2,4-TZD/HSA binding was an exothermic and spontaneous reaction. Molecular docking analysis revealed that 2,4-TZD binds to HSA subdomain IB and that the complex formed is stabilized by van der Waal\'s interactions and hydrogen bonds. Molecular dynamics simulation confirmed the stability of the HSA-TZD complex. Further, circular dichroism and 3D fluorescence studies showed that the global conformation of HSA was slightly altered by 2,4-TZD binding, enhancing its stability. The results obtained herein further help in understanding the pharmacokinetic properties of thiazolidinedione.
摘要：
噻唑烷二酮衍生物(TZDs)因其药理作用而备受关注。例如,据报道,某些TZD通过结合和激活PPAR(过氧化物酶体增殖物激活受体)改善II型糖尿病.尽管如此，没有关于杂环2,4-噻唑烷二酮(2,4-TZD)部分与血清白蛋白之间相互作用的信息，这可能会影响TZDs的药代动力学和药效学。在这项研究中,我们研究了2,4-TZD与人血清白蛋白（HSA）的结合。本征荧光光谱显示，2,4-TZD和HSA之间的结合化学计量比为1：1，在298K时的结合常数（Kb）为1.69±0.15×103M-1。等温滴定量热法研究表明，2,4-TZD/HSA结合是放热和自发反应。分子对接分析显示2,4-TZD与HSA亚结构域IB结合，并且形成的复合物通过范德华相互作用和氢键稳定。分子动力学模拟证实了HSA-TZD复合物的稳定性。Further,圆二色性和3D荧光研究表明，2,4-TZD结合略微改变了HSA的整体构象，增强其稳定性。本文获得的结果进一步有助于理解噻唑烷二酮的药代动力学性质。
