橙皮苷通过与成纤维细胞生长因子21（FGF - 21）、α -淀粉酶和α -葡萄糖苷酶结合消除双酚A的内分泌干扰作用：一项计算机分子研究

Hesperidin abrogates bisphenol A endocrine disruption through binding with fibroblast growth factor 21 (FGF-21), α-amylase and α-glucosidase: an in silico molecular study.

作者信息

Aja P M, Awoke J N, Agu P C, Adegboyega A E, Ezeh E M, Igwenyi I O, Orji O U, Ani O G, Ale B A, Ibiam U A

机构信息

Department of Biochemistry, Faculty of Science, Ebonyi State University, Abakaliki, Nigeria.

Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK.

出版信息

J Genet Eng Biotechnol. 2022 Jun 1;20(1):84. doi: 10.1186/s43141-022-00370-z.

DOI:10.1186/s43141-022-00370-z

PMID:35648239

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9160168/

Abstract

BACKGROUND

Fibroblast growth factor 21 (FGF-21), alpha-amylase, and alpha-glucosidase are key proteins implicated in metabolic dysregulations. Bisphenol A (BPA) is an environmental toxicant known to cause endocrine dysregulations. Hesperidin from citrus is an emerging flavonoid for metabolic diseases management. Through computational approach, we investigated the potentials of hesperidin in abrogating BPA interference in metabolism. The 3D crystal structure of the proteins (FGF-21, α-amylase, and α-glucosidase) and the ligands (BPA and hesperidin) were retrieved from the PDB and PubChem database respectively. Using Autodock plugin Pyrx, molecular docking of the ligands and individual proteins were performed to ascertain their binding affinities and their potentials to compete for the same binding site. Validation of the docking study was considered as the ability of the ligands to bind at the same site of each proteins. The docking poses were visualized using UCSF Chimera and Discovery Studio 2020, respectively to reveal each of the protein-ligands interactions within the binding pockets. Using SwissAdme and AdmeSar servers, we further investigated hesperidin's ADMET profile. Hesperidin used was purchased commercially.

RESULTS

Hesperidin and BPA competitively bound to the same site on each protein. Interestingly, hesperidin had greater binding affinities (Kcal/mol) - 5.80, - 9.60, and - 9.60 than BPA (Kcal/mol) - 4.40, - 7.20, - 7.10 for FGF-21, α-amylase, and α-glucosidase respectively. Visualizations of the binding poses showed that hesperidin interacted with stronger bonds than BPA within the proteins' pockets. Although hesperidin violated Lipinski rule of five, this however can be optimized through structural modifications.

CONCLUSIONS

Hesperidin may be an emerging natural product with promising therapeutic potentials against metabolic and endocrine derangement.

摘要

背景

成纤维细胞生长因子21（FGF - 21）、α - 淀粉酶和α - 葡萄糖苷酶是与代谢失调相关的关键蛋白质。双酚A（BPA）是一种已知会导致内分泌失调的环境毒物。柑橘中的橙皮苷是一种用于管理代谢疾病的新兴类黄酮。通过计算方法，我们研究了橙皮苷消除BPA对代谢干扰的潜力。分别从蛋白质数据银行（PDB）和化学数据库（PubChem）检索蛋白质（FGF - 21、α - 淀粉酶和α - 葡萄糖苷酶）和配体（BPA和橙皮苷）的三维晶体结构。使用自动对接插件Pyrx对配体和单个蛋白质进行分子对接，以确定它们的结合亲和力以及竞争相同结合位点的潜力。对接研究的验证被视为配体在每种蛋白质的同一位点结合的能力。分别使用加州大学旧金山分校（UCSF）的Chimera和Discovery Studio 2020可视化对接姿势，以揭示结合口袋内每种蛋白质 - 配体相互作用。使用SwissAdme和AdmeSar服务器，我们进一步研究了橙皮苷的药物代谢动力学（ADMET）特性。所使用的橙皮苷是商业购买的。

结果

橙皮苷和BPA竞争性地结合到每种蛋白质的同一位点。有趣的是，对于FGF - 21、α - 淀粉酶和α - 葡萄糖苷酶，橙皮苷分别具有比BPA更高的结合亲和力（千卡/摩尔）—— - 5.80、 - 9.60和 - 9.60，而BPA的结合亲和力分别为 - 4.40、 - 7.20、 - 7.10。结合姿势的可视化显示，在蛋白质口袋内，橙皮苷与比BPA更强的键相互作用。尽管橙皮苷违反了Lipinski的五规则，但这可以通过结构修饰进行优化。