In silico screening of potential agonists of a glucagon-like peptide-1 receptor among female sex hormone derivatives

Abstract

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.

Communicated by Ramaswamy H. Sarma

Keywords:

• Glucagon-like peptide-1 (GLP-1)
• molecular docking
• molecular dynamics
• hormone–receptor complex
• estrogen receptor modulators
• metabolism

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

MN gratefully acknowledges the financial support from National Competence Centre for Research (NCCR), ‘Bioinspired Materials’. This study was supported by the project UNITe—BG05M2OP001-1.001-0004 funded by the OP SESG and co-funded by the EU Structural and Investment Funds. MN was supported by the European Union—NextGenerationEU through the National Recovery and Resilience Plan of the Republic of Bulgaria, project No. BG-RRP-2.004-0008-C01.