Sodium-glucose co-transporter 2 (SGLT-2) is a major transport protein responsible for reabsorption of glucose from the kidney back to the bloodstream. Inhibiting this protein effectively lowers the glucose level of diabetic patients; however, the use of synthetic SGLT-2 inhibitors has been linked to some serious adverse effects. There is a need to identify safer alternatives that are equally or more effective as the current inhibitor drugs. Phytochemicals are known for their efficacy as herbal remedies, but these molecules remain underexplored as source of therapeutic agents. In this study, we performed in silico screening to identify potential SGLT-2 inhibitors from the 21 phytochemicals from Centella asiatica. Docking results identified eleven compounds with estimated binding energies comparable to that of known inhibitors drugs. The stability of the complexes was then elucidated using 100 ns MD simulations. From our dynamic binding free energy calculations using MM/PBSA, asiaticoside, betulinic acid, centellasapogenol, methyl brahmate, and rutin exceeded at least one of the binding energies of the reference compounds, which highlights their strong affinity towards SGLT-2. Among the five, betulinic acid, centellasapogenol, and methyl brahmate maintained their structural stability to the same extent as the references and exhibited better oral bioavailability and excellent drug-like properties. Because of these results, it is recommended to prioritize betulinic acid, centellasapogenol, and methyl brahmate in future in vitro and in vivo studies to verify their potential as inhibitor drugs for diabetes therapies.

Current oral medications for type 2 diabetes target a single main physiological mechanism. They either activate or inhibit receptors to enhance insulin sensitivity, increase insulin secretion, inhibit glucose absorption, or inhibit glucose production. In advanced stages, combination therapy may be required because of the limited efficacy of single-target drugs; however, medications are becoming more costly, and there is also the risk of developing the combined side effects of each drug. Thus, identifying a multi-target drug may be the best strategy to improve treatment efficacy. This study sees the potential of 2657 Filipino phytochemicals as a source of natural inhibitors against four targets of diabetes: PTP1B, DPP-4, SGLT-2, and FBPase. Different computer-aided drug discovery techniques, including ADMET profiling, DFT optimization, molecular docking, MD simulations, and MM/PBSA energy calculations, were employed to elucidate the stability and determine the binding affinity of the candidate ligands. Through in silico methods, we have identified seven potential natural inhibitors against PTP1B, DPP-4, and FBPase, and ten against SGLT-2. Eight plants containing at least one natural inhibitor of each protein target were also identified. It is recommended to further investigate the plants’ potential to be transformed into a safe and scientifically validated multi-target drug for diabetes therapies.