Catechins anti-diabetic actions are mediated via multiple receptors, a mechanism deduced via molecular docking and dynamic simulations

Diabetes mellitus is a growing burden that affects a large proportion of the population worldwide, with long-term complications that cause a devastating effect on the function of various organs. The currently available treatments lack optimum therapeutic goals, increasing the need for new drug discovery. Catechins are natural flavonoids that demonstrate anti-diabetic effects; however, catechin’s mechanism of action remains unclear. This study was aimed to unleash the molecular mechanism behind the catechin’s effect on blood glucose levels. For that, we explored the capability of some catechins to bind and interact with glucagon-like peptide-1 receptor-1, pancreatic ATP-sensitive potassium channel, dipeptidyl peptidase-4, and sodium-glucose transporter-2, which is essential for euglycemia, using molecular docking screening and dynamic simulations. The results showed that all the tested catechins are potential sodium-glucose transporter-2 inhibitors, a mechanism revealed for the first time, and glucagon-like peptide-1 receptor-1 agonists with various affinities to these receptors. Moreover, among these compounds, (−)-Epigallocatechin 3-O-gallate, (−)-Gallocatechin 3-O-gallate demonstrated the ability to act as an ATP-sensitive potassium channel inhibitor, and dipeptidyl peptidase-4 inhibitor in addition to the previously mentioned mechanisms. The discovery introduces (−)-gallocatechin 3-O-gallate and (−)-Epigallocatechin 3-O-gallate as a hot subject for research, as the compounds require further optimization to initiate further pre-clinical and clinical studies.糖尿病（Diabetes mellitus）已成为日益加重的全球公共卫生负担，影响全球大量人口，其引发的长期并发症会对多种脏器功能造成毁灭性损害。当前临床可用治疗方案难以达成最佳治疗目标，使得新药研发的需求愈发迫切。儿茶素（Catechins）是一类天然黄酮类化合物，已被证实具备抗糖尿病活性，但其具体作用机制仍未阐明。本研究旨在揭示儿茶素调控血糖水平背后的分子机制。为此，我们采用分子对接筛选与分子动力学模拟技术，探究了多种儿茶素与血糖稳态关键靶点的结合与相互作用能力，这些靶点包括胰高血糖素样肽-1受体-1（glucagon-like peptide-1 receptor-1）、胰腺ATP敏感性钾通道（pancreatic ATP-sensitive potassium channel）、二肽基肽酶-4（dipeptidyl peptidase-4）以及钠-葡萄糖协同转运蛋白2（sodium-glucose transporter-2）。研究结果表明，所有受试儿茶素均为潜在的钠-葡萄糖协同转运蛋白2抑制剂（该作用机制为首次报道），同时可作为对上述受体具有不同亲和力的胰高血糖素样肽-1受体-1激动剂。此外，在受试化合物中，(-)-表没食子儿茶素没食子酸酯与(-)-没食子儿茶素没食子酸酯还可作为胰腺ATP敏感性钾通道抑制剂与二肽基肽酶-4抑制剂，进一步丰富了前述作用机制。本研究将(-)-没食子儿茶素没食子酸酯与(-)-表没食子儿茶素没食子酸酯确立为重要研究热点，但上述化合物仍需开展进一步优化，方可启动后续临床前与临床研究。