Extracts of selected Lamiaceae species as promising antidiabetics: Chemical profiling, in vitro and in silico approach combined with dynamical modeling

Highlights

• Several Lamiaceae representatives exhibited antidiabetic potential in vitro.

• Kinetic study revealed mixed inhibition of α-glucosidase by M. piperita extract.

• Transition of experimental yeast data into predicted human α-glucosidase inhibition.

• Dynamical model of inhibition revealed S. montana as promising antidiabetic source.

Abstract

Diabetes mellitus has been recognized as one of the most challenging public health problems in the 21st century. The present study aimed to investigate the antidiabetic potential of 18 selected Lamiaceae representatives on yeast α-glucosidase and further translate experimental data into predicted human α-glucosidase inhibition. Since conventional antidiabetic drugs exhibit numerous unavoidable side effects, plant extracts are being increasingly explored as safer alternatives. Plant extracts were prepared by maceration, characterized by liquid chromatography-mass spectrometry (LC-MS), and subjected to in vitro determination of yeast α-glucosidase inhibitory potential, after which the kinetic study of one of the most potent extracts (Mentha × piperita) was performed. Docking simulations were done on both yeast and human α-glucosidase to explore binding modes and energies of the secondary metabolites identified in the examined extracts. Finally, the dynamical model has been constructed (adjR² = 0.9885) and applied to explore extracts’ inhibition potential onto the human α-glucosidase. The constructed dynamical model revealed, for the first time, that different extracts of Satureja montana represent highly promising candidates for the prevention/treatment of diabetes mellitus. Therefore, the dynamical model described in this study represents a useful tool and a significant advance in the discovery of novel therapeutics with antidiabetic potential in humans.

Introduction

Diabetes is a common metabolic disorder, manifested by increased blood glucose levels – hyperglycemia and impaired metabolism of carbohydrates, proteins, and lipids (Behradmanesh et al., 2013). It occurs as a type 1 (an autoimmune disease characterized by insufficient endogenous insulin secretion by pancreatic β-cells) or type 2 diabetes (DT2), which involves insulin resistance and abnormal insulin secretion or action (up to 95 % of reported cases of diabetes) (Chinsembu, 2019, Lima et al., 2006). According to the World Health Organization, 180 million people worldwide are currently diagnosed with diabetes mellitus – DT2 (Javid et al., 2021), designating this metabolic disorder as one of the most challenging public health issues both nowadays and in the upcoming times.

Therapeutic strategies in the treatment of DT2 are predominantly based on the inhibition of α-glucosidase, which is the enzyme that catalyzes the final step of carbohydrate digestion in the intestine. This inhibition leads to delayed digestion and absorption of carbohydrates, thus suppressing postprandial hyperglycemia as one of the earliest metabolic abnormalities occurring in diabetes mellitus (Wang et al., 2015). Therefore, the inhibition of α-glucosidase can be considered a reliable approach for the treatment of carbohydrate intake disorders, such as diabetes and obesity (Chinsembu, 2019, Mahdi et al., 2020, Sales et al., 2012, Tundis et al., 2010). One of the widely used inhibitors of α-glucosidase is acarbose (a pseudotetra-saccharide produced by Actinoplanes sp. in the fermentation process), which slows down oligosaccharide-degradation and glucose-uptake in the small intestine (Sales et al., 2012, Tundis et al., 2010, Wang et al., 2021). However, higher doses can cause various side effects, such as hypoglycemia, liver dysfunction, lactic acidosis, bloating, and diarrhea. These side effects are also characteristic of many other DT2 commercial drugs (metformin, sulfonylureas, etc.) (Bodmer et al., 2008). Consequently, a plethora of investigations is now focusing on discovering safer alternatives for DT2 control, where plant extracts arise as fruitful sources of new therapeutics (Barbosa et al., 2013, Jacob and Narendhirakannan, 2019, Tundis et al., 2010).

Lamiaceae represents one of the largest families of flowering plants, comprising 236 genera and approximately 7200 species (Esra et al., 2011, Raja, 2012). A number of these plants and corresponding secondary metabolites are highly appreciated in food, agricultural, cosmetic, as well as in pharmacological industries (Trivellini et al., 2016). Bearing that in mind, miscellaneous in vitro and in vivo studies have already shown considerable antidiabetic effects of different Lamiaceae species (Afolayan and Sunmonu, 2010, Casanova et al., 2014, Castellano et al., 2013, Jadhav and Puchchakayala, 2012, Mnonopi et al., 2012, Wu et al., 2014), which can be attributed to the inherent abundance of biologically active compounds. Among these, phenolic compounds are the ones most frequently identified and analyzed. Phytochemicals such as phenolic acids, flavonoids, triterpenoids, and others have been continuously used in the management of metabolic disorders – diabetes mellitus and its complications (Bahadoran et al., 2013, Menezes et al., 2017). The underlying mechanisms of these phytoconstituents’ antidiabetic effects include the inhibition of the α-glucosidase activity, hypoglycemic activity, oxygen radical scavenging activity, modulation of lipid status, stimulation of insulin secretion and activation, while some of the secondary metabolites found in these plants also increase insulin and glucose transporter gene expression levels in INS-1 (insulin-secreting cell line 1) cells.

The present study aimed to investigate the antidiabetic potential of 18 Lamiaceae representatives cultivated in Serbia on yeast α-glucosidase and further translate obtained experimental data into predicted human α-glucosidase inhibition, by combining an in silico approach with dynamical modeling. Lamiaceae extracts (70 % methanol, 70 % ethanol, and water) were obtained by classical maceration and chemically characterized via Liquid Chromatography-Mass Spectrometry (LC-MS). Extracts were subjected to in vitro determination of yeast α-glucosidase inhibitory potential and the most potent extract was further explored to reveal the mode of enzyme inhibition. Based on the kinetic results, docking simulations were performed on both yeast and human α-glucosidase to examine the binding mode and energies of the secondary metabolites identified in the extracts. Finally, the dynamical model, which successfully describes the binding of secondary metabolites to yeast α-glucosidase and its inhibition, has been constructed. The proposed model was applied to predict the inhibitory potential of the explored Lamiaceae extract onto the human α-glucosidase, providing a significant advance in the discovery of compounds with antidiabetic potential in humans.