原发性干燥综合征(pSS)是一种全身性自身免疫性疾病,可导致唾液分泌减少,主要影响女性由于雌激素缺乏。雌激素受体α(ERα)通过雌激素反应元件依赖性信号通路介导水通道蛋白5(AQP5)基因的表达,使ERα成为pSS的关键药物靶标。已经报道了几种类黄酮具有治疗pSS的潜力。本研究旨在筛选和比较使用AutoDock与ERα结合的黄酮类化合物,为黄酮类化合物处理pSS提供依据。在这项研究中检查了六种代表性黄酮类化合物的雌激素潜力。分子对接显示,所有六种类黄酮对ERα的结合能均小于-5.6kcal/mol。芹菜素,柚皮苷,和大豆黄酮是最高的三种类黄酮,其结合能甚至更低,分别为-7.8,-8.09和-8.59kcal/mol,分别。与阳性对照雌二醇相似,芹菜素,柚皮苷,和大豆苷元在活性位点显示与GLU353,GLY521和HIS524的氢键相互作用。荧光素酶报告基因测定的结果表明芹菜素,柚皮苷,和大豆苷元显着增强了PGL3/AQP5启动子中雌激素受体元件(ERE)的转录。此外,使用GROMACS进行100ns时间尺度的分子动力学模拟显示,芹菜素-ERα的结合相对稳定,柚皮素-ERα,和大豆苷元-ERα。机械上,同源性建模表明GLU353,GLY521和HIS524是ERα发挥雌激素作用的关键残基。进一步验证芹菜素对pSS模型口干的治疗效果。总之,这些结果表明芹菜素的雌激素和PSS治疗潜力,柚皮苷,还有Daidzein.
Primary Sjögren\'s Syndrome (pSS) is a systemic autoimmune disease that leads to reduced saliva production, primarily affecting women due to estrogen deficiency. The estrogen receptor α (
ERα) plays a crucial role in mediating the expression of the aquaporin 5 (AQP5) gene through the estrogen response element-dependent signaling pathway, making
ERα a key drug target for pSS. Several flavonoids have been reported to have the potential to treat pSS. This study aimed to screen and compare flavonoids binding to
ERα using AutoDock, providing a basis for treating pSS with flavonoids. The estrogenic potential of six representative flavonoids was examined in this study. Molecular docking revealed that the binding energy of all six flavonoids to
ERα was less than -5.6 kcal/mol. Apigenin, naringenin, and daidzein were the top three flavonoids with even lower binding energies of -7.8, -8.09, and -8.59 kcal/mol, respectively. Similar to the positive control estradiol, apigenin, naringenin, and daidzein showed hydrogen bond interactions with GLU353, GLY521, and HIS524 at the active site. The results of luciferase reporter assays demonstrated that apigenin, naringenin, and daidzein significantly enhanced the transcription of estrogen receptor element (ERE) in the PGL3/AQP5 promoter. Furthermore, molecular dynamics simulations using GROMACS for a time scale of 100 ns revealed relatively stable binding of apigenin-ERα, naringenin-
ERα, and daidzein-
ERα. Mechanistically, homology modeling indicated that GLU353, GLY521, and HIS524 were the key residues of ERα exerting an estrogenic effect. The therapeutic effect of apigenin on dry mouth in pSS models was further validated. In conclusion, these results indicate the estrogenic and pSS therapeutic potential of apigenin, naringenin, and daidzein.