Evaluation of Traditionally Used Medicinal Plants for Repurposing as Therapeutic Agents Targeting Human Diseases

Abstract

In silico drug design is a cost-effective method for identifying lead compounds before experimental validation. Owing to their lower toxicity and structural diversity, phytochemicals are increasingly being used as multitarget agents to treat complex disorders, such as diabetes and neurodegeneration. Using 70% ethanolic extracts, five traditionally medicinal plants including Foeniculum vulgare, Trachyspermum ammi, Mentha piperita, Coriandrum sativum, and Cuminum cyminum were investigated in this study. The identified phytochemicals through GC-MS analysis were molecularly docked using Schrödinger Maestro Version 2025-2. The binding affinities of acetylcholinesterase (AChE; PDB ID: 1eve) for neurodegeneration disorders and α-glucosidase (PDB ID: 3top) for diabetes were evaluated using donepezil and α-acarbose as reference inhibitors. The pharmacokinetics and toxicity profiles were estimated using the pkCSM platform. TMA24 exhibited the strongest affinity for AChE (docking score: –8.59 kcal/mol), outperforming donepezil (–7.91 kcal/mol) in the docking study. The enhanced binding was attributed to sulfur-mediated π–π stacking, hydrophobic interactions, and hydrogen bonding. TMA1 was the best-performing phytochemical (–6.42 kcal/mol), slightly lower than α-acarbose which had the highest interaction with α-glucosidase (–6.52 kcal/mol). The other compounds, PM3, TMA5, and PM10 also exhibited appreciated binding activities with the receptor proteins. According to the ADMET predictions, the phytochemicals exhibited superior intestinal absorption, CNS penetration, and Caco-2 permeability and have lower toxicity compared to the reference drugs. Therefore, the study highlighted that the reported druglike phytochemicals can act as the safer analogs against reference drugs such as donepezil and α-acarbose for the treatment of Alzheimer’s and diabetic diseases, respectively. In-vitro and in-vivo validation and molecular dynamics simulations are to be incorporated into future studies to increase further specificity and safety.