Johari Anahita, Moosavi-Movahedi Ali Akbar, Amanlou Massoud
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Daru. 2014 Dec 11;22(1):79. doi: 10.1186/s40199-014-0079-0.
Glycation of serum albumin and its consequence products were considered as an important factor in drug distribution and diabetic complications, therefore finding the glycation inhibitors and their inhibitory mechanisms became a valuable field of study. In this work, bovine serum albumin (BSA) became a subject as a model protein for analyzing the inhibitory mechanism of flavonoids, known as natural BSA glycation inhibitors in the early stage of glycation.
Firstly, for theoretical study, the three-dimensional model of BSA structure was generated by homology modeling and refined through molecular dynamic simulation. Secondly, several validation methods (statistical assessment methods and also neural network methods) by simultaneous docking study were employed for insurance about accuracy of our simulation. Then docking studies were performed for visualizing the relation between flavonoids' binding sites and BSA glycation sites besides, the correlation analyzes between calculated binding energy and reported experimental inhibitory IC50 values of the flavonoids set, was considered to explore their molecular inhibitory mechanism.
The quality assessment methods and simultaneous docking studies on interaction of quercetin (as the most studied flavonoids) with BSA and Human serum albumin (HAS), confirm the accuracy of simulation and the second stage of docking results which were in close agreement with experimental observations, suggest that the potential residues in flavonoids binding sites (which were place neighbor of tryptophan 212 within 5Ǻ) cannot be considered as one of glycation sites.
Based on the results, flavonoids don't participate in inhibitory interference mechanism, and also, the differentiation between complexes of flavonoids with BSA and HSA could destroy the speculation of using them as an exchangeable model protein in study of serum albumin and flavonoids interactions.
血清白蛋白的糖基化及其产物被认为是药物分布和糖尿病并发症的一个重要因素，因此寻找糖基化抑制剂及其抑制机制成为一个有价值的研究领域。在这项工作中，牛血清白蛋白（BSA）作为一种模型蛋白成为研究对象，用于分析黄酮类化合物的抑制机制，黄酮类化合物在糖基化早期被认为是天然的BSA糖基化抑制剂。
首先，为了进行理论研究，通过同源建模生成BSA结构的三维模型，并通过分子动力学模拟进行优化。其次，采用几种同时对接研究的验证方法（统计评估方法和神经网络方法）来确保模拟的准确性。然后进行对接研究，以可视化黄酮类化合物结合位点与BSA糖基化位点之间的关系，此外，考虑黄酮类化合物组计算的结合能与报道的实验抑制IC50值之间的相关性分析，以探索其分子抑制机制。
对槲皮素（作为研究最多的黄酮类化合物）与BSA和人血清白蛋白（HSA）相互作用的质量评估方法和同时对接研究，证实了模拟的准确性，对接结果的第二阶段与实验观察结果密切一致，表明黄酮类化合物结合位点中的潜在残基（位于色氨酸212附近5Ǻ内）不能被视为糖基化位点之一。
基于这些结果，黄酮类化合物不参与抑制干扰机制，此外，黄酮类化合物与BSA和HSA复合物之间的差异可能会破坏在血清白蛋白和黄酮类化合物相互作用研究中使用它们作为可互换模型蛋白的推测。
