Nedyalkova Miroslava, Robeva Ralitsa, Romanova Julia, Yovcheva Kirila, Lattuada Marco, Simeonov Vasil
Department of Chemistry, Fribourg University, Fribourg, Switzerland.
Department of Inorganic Chemistry, Faculty of Chemistry and Pharmacy, University of Sofia 'St. Kl. Ohridski', Sofia, Bulgaria.
J Biomol Struct Dyn. 2024 Apr 8:1-12. doi: 10.1080/07391102.2024.2330714.
Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that exerts its pleiotropic effects through a specific GLP-1 receptor (GLP-1R). The hormone-receptor complex might regulate glucose-dependent insulin secretion, and energy homeostasis; moreover, it could decrease inflammation and provide cardio- and neuroprotection. Additionally, the beneficial influence of GLP-1 on obesity in women might lead to improvement of their ovarian function. The links between metabolism and reproduction are tightly connected, and it is not surprising that different estrogen derivatives, estrogen-receptor modulator (SERM) and progestins used for gonadal and oncological disorders might influence carbohydrate and lipid metabolism. However, their possible influence on the GLP-1R has not been studied. The docking scores and top-ranked poses of raloxifene were much higher than those observed for other investigated SERMs and estradiol per se. Among different studied progestins, drospirenone showed slightly higher affinity to GLP-1R. Herein, the same data set of the drugs is evaluated by molecular dynamics (MD) simulations and compared with the obtained docking result. Notably, it is demonstrated that the used docking protocol and the applied MD calculations ranked the same ligand (raloxifene) as the best one. In the present study, raloxifene might exert an allosteric influence on GLP-1R signaling, which might contribute to potential beneficial effects on metabolism and weight regulation. However, further experimental and clinical studies are needed to reveal if the GLP-1R modulation has a real biological impact.
胰高血糖素样肽-1（GLP-1）是一种肠道激素，通过特定的GLP-1受体（GLP-1R）发挥其多效性作用。激素-受体复合物可能调节葡萄糖依赖性胰岛素分泌和能量稳态；此外，它还可以减轻炎症并提供心脏和神经保护作用。此外，GLP-1对女性肥胖的有益影响可能会改善她们的卵巢功能。代谢与生殖之间的联系紧密相连，用于性腺和肿瘤疾病的不同雌激素衍生物、雌激素受体调节剂（SERM）和孕激素可能会影响碳水化合物和脂质代谢，这并不奇怪。然而，它们对GLP-1R的可能影响尚未得到研究。雷洛昔芬的对接分数和排名靠前的构象比其他研究的SERM和雌二醇本身观察到的要高得多。在不同研究的孕激素中屈螺酮对GLP-1R的亲和力略高。在此，通过分子动力学（MD）模拟评估相同的药物数据集，并与获得的对接结果进行比较。值得注意的是，结果表明所使用的对接协议和应用的MD计算将相同的配体（雷洛昔芬）列为最佳配体。在本研究中，雷洛昔芬可能对GLP-1R信号传导产生变构影响，这可能有助于对代谢和体重调节产生潜在的有益作用。然而，需要进一步的实验和临床研究来揭示GLP-1R调节是否具有真正的生物学影响。
