Department of Pharmaceutical Chemistry, Semmelweis University, Research Group of Drugs of Abuse and Doping Agents, Hungarian Academy of Sciences, Hőgyes Endre U. 9, Budapest 1092, Hungary.
Eur Biophys J. 2013 Sep;42(9):721-30. doi: 10.1007/s00249-013-0921-1. Epub 2013 Aug 2.
Interactions between thyroid hormone α and β receptors and the eight protonation microspecies of each of the main thyroid hormones (thyroxine, liothyronine, and reverse liothyronine) were investigated and quantitated by molecular modeling. Flexible docking of the various protonation forms of thyroid hormones and high-affinity thyromimetics to the two thyroid receptors was carried out. In this method the role of the ionization state of each basic site could be studied in the composite process of molecular recognition. Our results quantitate at the molecular level how the ionization state and the charge distribution influence the protein binding. The anionic form of the carboxyl group (i.e., carboxylate site) is essential for protein binding, whereas the protonated form of amino group worsens the binding. The protonation state of the phenolate plays a less important role in the receptor affinity; its protonation, however, alters the electron density and the concomitant stacking propensity of the aromatic rings, resulting in a different binding score. The combined results of docking and microspeciation studies show that microspecies with the highest concentration at the pH of blood are not the strongest binding ones. The calculated binding free energy values can be well interpreted in terms of the interactions between the actual sites of the microspecies and the receptor amino acids. Our docking results were validated and compared with biological data from the literature. Since the thyroid hormone receptors influence several physiologic functions, such as metabolic rate, cholesterol and triglyceride levels, and heart frequency, our binding results provide a molecular basis for drug design and development in related therapeutic indications.
通过分子建模研究了甲状腺激素 α 和 β 受体与主要甲状腺激素（甲状腺素、三碘甲状腺原氨酸和反式三碘甲状腺原氨酸）的每个质子化微种的八种质子化微种之间的相互作用，并对其进行了定量。对各种甲状腺激素和高亲和力甲状腺模拟物的各种质子化形式与两种甲状腺受体的柔性对接进行了研究。在这种方法中，可以研究每个碱性位点的电离状态在分子识别的复合过程中的作用。我们的结果从分子水平量化了电离状态和电荷分布如何影响蛋白质结合。羧基的阴离子形式（即羧酸盐部位）对于蛋白质结合是必需的，而氨基的质子化形式会降低结合能力。酚盐的质子化状态在受体亲和力中起着次要作用；然而，它会改变芳环的电子密度和伴随的堆积倾向，从而导致不同的结合分数。对接和微种研究的综合结果表明，在血液 pH 值下浓度最高的微种并不是结合最强的微种。计算得到的结合自由能值可以很好地用微种的实际部位与受体氨基酸之间的相互作用来解释。我们的对接结果经过验证，并与文献中的生物学数据进行了比较。由于甲状腺激素受体影响多种生理功能，如代谢率、胆固醇和甘油三酯水平以及心率，因此我们的结合结果为相关治疗适应症的药物设计和开发提供了分子基础。
