Recent Developments in Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors as a Valuable Tool in the Treatment of Type 2 Diabetes Mellitus.

In today's world, metabolic disorders are much dominant, and among them, diabetes is causing the highest rate of mortality. There is no cure for diabetes, while treatment could be done either by insulin therapy or oral antidiabetic drug. Oral antidiabetic agents target pathogenic factors like receptors, enzymes, genes and proteins involved in diabetes progression. Among them, recently, sodium-glucose co-transporters (SGLTs) have been recognized for their potential to effectively treat Type 2 diabetes mellitus. SGLTs are classified as SGLT-1 and SGLT-2, and among them, SGLT-2 is a major transporter which is involved in glucose reabsorption. Therefore, targeting SGLTs by its inhibitors could be a better choice to control the blood glucose level. Canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin are known to be SGLT-2 inhibitors. Herein, we discussed the current and future aspects of the development and applications of SGLT-2 inhibitors.

Insight into the interaction mechanism of human SGLT2 with its inhibitors: 3D-QSAR studies, homology modeling, and molecular docking and molecular dynamics simulations.

Human sodium-dependent glucose co-transporter 2 (hSGLT2) is a crucial therapeutic target in the treatment of type 2 diabetes. In this study, both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to generate three-dimensional quantitative structure-activity relationship (3D-QSAR) models. In the most accurate CoMFA-based and CoMSIA-based QSAR models, the cross-validated coefficients (r2cv) were 0.646 and 0.577, respectively, while the non-cross-validated coefficients (r2) were 0.997 and 0.991, respectively, indicating that both models were reliable. In addition, we constructed a homology model of hSGLT2 in the absence of a crystal structure. Molecular docking was performed to explore the bonding mode of inhibitors to the active site of hSGLT2. Molecular dynamics (MD) simulations and binding free energy calculations using MM-PBSA and MM-GBSA were carried out to further elucidate the interaction mechanism. With regards to binding affinity, we found that hydrogen-bond interactions of Asn51 and Glu75, located in the active site of hSGLT2, with compound 40 were critical. Hydrophobic and electrostatic interactions were shown to enhance activity, in agreement with the results obtained from docking and 3D-QSAR analysis. Our study results shed light on the interaction mode between inhibitors and hSGLT2 and may aid in the development of C-aryl glucoside SGLT2 inhibitors.