Holistic investigation of Cotula cinerea essential oil against diabetes: hypoglycemic activity, enzymatic inhibition, GC-MS characterization, ADMET forecasting, MD simulations, and DFT insights

Abstract

Diabetes mellitus is a prevalent metabolic disorder characterized by impaired glucose metabolism. This study investigates the anti-diabetic potential of Cotula cinerea essential oil (EO) through in vivo, in vitro, and computational methodologies. In vitro enzyme inhibition assays demonstrated that C. cinerea EO effectively inhibits α-amylase and α-glucosidase, indicating its potential role in glucose regulation. In vivo studies further confirmed its hypoglycemic effects. GC–MS analysis identified 31 bioactive compounds within the EO. Molecular docking studies revealed that six of these compounds exhibited strong binding affinities to α-amylase and α-glucosidase, comparable to those of the standard drug acarbose (ARE). Among them, cis-verbenyl acetate (CVA) and β-terpineol (βTP) showed the highest docking scores against both enzymes. ADMET analysis confirmed their favorable pharmacokinetic properties, drug-likeness, and low toxicity risks. Molecular dynamics simulations demonstrated the stable binding of CVA and βTP with both enzymes, exhibiting lower RMSD and RMSF values compared to ARE, along with favorable Rg and SASA parameters. MM-PBSA calculations further validated their strong binding affinities. Density Functional Theory calculations provided deeper insights into the electronic characteristics of CVA and βTP, revealing their frontier molecular orbitals distributions and energy gap (∆E) values. The molecular electrostatic potential analysis identified key electron-rich and electron-deficient regions, suggesting potential interaction sites with the target enzymes. The observed reduction in ∆E values under aqueous conditions indicated increased molecular stability and reactivity within physiological environments, further supporting their role in enzyme inhibition. Overall, this study highlights C. cinerea EO as a promising natural source for diabetes management. The integration of in vivo, in vitro, and computational approaches offers compelling evidence for its therapeutic potential. Nevertheless, further experimental validation is necessary to assess its clinical applicability.