Antidiabetic potency of glimepiride and naringin: an <i>in silico</i> and <i>in vitro</i> investigation

Glimepiride (GLM) is one of the potential antidiabetic drugs used in clinics for a long time. It is currently used in combination with metformin along with other drugs, but has shown various complications in patients from long-term use. Thus, the hypothesis is to use a lower dose of GLM with a non-toxic class of flavonoid, naringin (NARN), for better therapy with minimal side-effects. Initially, we assessed the binding efficacy of GLM and NARN against nine putative target enzymes using AutoDock 4.2 software. We also analysed the drug chemistry, drug-ability, and cytotoxicity, as well as performed molecular dynamic (MD) simulation at 100 ns with individual and combination states using GROMACS-2022 software. Both candidates showed higher binding efficacy, especially against the AKT-serine/threonine kinase-1 (AKT1) target enzyme (-11.85 kcal/mol), and demonstrated higher stability and compatibility with AKT1 from MD-simulation (based on RMSD, Rg, RMSF, and H-bond plots) in combination than individual form. The <i>in vitro</i> cytotoxicity with human embryonic kidney (HEK-293) cells suggested 100 µg/mL (observed 80% of the cell viability) as a non-toxic dose for further study. Alpha-amylase, alpha-glucosidase, and DPP-IV inhibition assays revealed that both GLM and NARN inhibited up to 60% at 100 µg/mL in a concentration-dependent manner. At the end, selecting a lower dose of GLM and a higher dose of NARN (2:8 v/v ratio) showed up to 87% inhibition at 100 µg/mL. Both <i>in silico</i> and <i>in vitro</i> studies suggest that the investigated formulation could be a potential and non-toxic dose for diabetics.