Comprehensive in silico investigation of Cucumis sativus L. phytoconstituents through molecular docking, molecular dynamics simulation, and ADMET analysis targeting the GABA receptor

Cucumis sativus L. is a medicinal plant that contains diverse bioactive phytochemicals with potential pharmacological relevance. This study aimed to investigate the effects of C. sativus phytoconstituents on the human GABA receptor (PDB ID: ۶X۳U) using molecular docking, molecular dynamics (MD) simulation, and ADMET analysis, supported by preliminary phytochemical screening of the leaf extract. The methanolic leaf extract was subjected to qualitative phytochemical screening, and selected C. sativus phytoconstituents were evaluated by molecular docking using AutoDock Vina in PyRx. The top-ranked compound was further assessed by a ۱۰۰ ns MD simulation using the Desmond module of Schrödinger, and its physicochemical, pharmacokinetic, medicinal chemistry, and toxicity profiles were predicted using ADMETLab ۳.۰ and ProTox-III software. Phytochemical screening confirmed the presence of reducing sugars, steroids, tannins, alkaloids, glycosides, flavonoids, saponins, and phenols, while terpenoids were absent. Among the screened compounds, apigenin ۷-O-(۶''-O-p-coumaroylglucoside) showed the most favorable predicted binding affinity (−۱۱.۳ kcal/mol), followed by orientin (−۱۰.۴ kcal/mol), quercetin ۳-O-glucoside (−۱۰.۰ kcal/mol), kaempferol ۳-O-rhamnos (−۹.۴ kcal/mol), and Cucumerin A (−۹.۲ kcal/mol), compared with −۸.۹ kcal/mol for the native ligand. The ۱۰۰ ns MD simulation supported the stability of the predicted protein–ligand complex, with the RMSD remaining below ۳.۰ Å, limited binding-site residue fluctuations, and persistent hydrogen-bond interactions. ADMET analysis indicated a comparatively balanced predicted profile for the lead compound; however, its relatively high molecular weight and polar surface area may limit membrane permeability and BBB penetration, with additional predicted toxicity liabilities. Thus, Apigenin ۷-O-(۶''-O-p-coumaroylglucoside) may be considered a potential GABA receptor-targeting lead rather than a confirmed receptor modulator or a CNS drug candidate. These computational findings require experimental validation of receptor binding, pharmacological activity, pharmacokinetic behavior, blood-brain barrier (BBB) exposure, and toxicity.

کلیدواژه ها:

Cucumis sativus ، GABA receptor ، Molecular docking ، Molecular Dynamics Simulation ، ADMET analysis