GC-MS Based Phytochemical Profiling and Integrated In vitro and In silico Evaluation of Cucurbita maxima Leaf Extract Against Diabetes and Androgen Receptor Dependent Prostate Cancer

Abstract Prostate cancer and diabetes mellitus pose significant therapeutic problems, highlighting the need for new bioactive substances that might alter both metabolic and oncogenic pathways. In this study, we evaluated the α-amylase inhibitory activity of a plant-derived sample and investigated its binding efficacy against a diabetes-related target and androgen receptor using molecular docking and molecular dynamics (MD) simulations. The sample demonstrated concentration-dependent α-amylase inhibition, with inhibitory activity increasing from 11.44 ± 6.17% at 1.25 mg/mL to 68.32 ± 0.17% at 10 mg/mL, corresponding to an estimated IC 50 value of 5.27 mg/mL compared with 3.50 mg/mL for the reference standard. Molecular docking of 147 compounds identified several favorable ligand–target interactions. For the diabetes-related target, Vitamin k1(20),heptafluorobutyric derive (CMP148) exhibited the highest predicted binding affinity (− 9.8 kcal/mol), followed by Stigmasterol (CMP88) (− 8.9 kcal/mol), both of which surpassed the predicted binding affinity of acarbose (− 7.7 kcal/mol). Against the androgen receptor, CMP88 and Desmosterol (CMP91) showed strong binding affinities of − 8.6 and − 8.5 kcal/mol, respectively, outperforming reference drugs abiraterone (− 8.1 kcal/mol) and bicalutamide (− 7.7 kcal/mol). Subsequent 100-ns MD simulations demonstrated generally stable protein–ligand complexes, with RMSD values consistently below 3 Å. CMP88 exhibited optimal dynamic stability for the diabetes-related target, yielding MM/GBSA binding energies of − 32.52, − 34.86, and − 30.97 kJ/mol across evaluated time points. For the androgen receptor, CMP91 displayed the strongest dynamic profile, featuring a mean RMSD of 1.267 ± 0.147 Å and an MM/GBSA binding energy of − 35.35 kJ/mol at 50 ns. These finding demonstrate concentration dependent α – amylase inhibition and highlight CMP88 and CMP91 as promising candidates for the diabetes- related and androgen receptor targets, respectively, requiring additional biochemical and cellular confirmation.