Acharya_2025_Chem.Biodivers__e202403374

Alzheimer's disease (AD) is primarily caused by abnormal protein accumulation, such as beta-amyloid plaques and tau tangles, leading to neuronal damage via oxidative stress, neuroinflammation, synaptic dysfunction, and progressive brain atrophy. It is crucial to address and explore alternative therapeutic candidates. Based on traditional reports, the present study investigates the phytochemicals present in Benincasa hispida (Thunb.) Cogn. seeds and their potency against AD. Primarily, four different solvent systems have been used for crude extraction, and simultaneously fifty-one phytochemicals (BH_P1 to BH_P51) have been selected through chromatography-mass spectrometry (GC-MS) for further study. Five putative AD-associated targets, acetylcholinesterase (AChE), butyryl cholinesterase (BChE), estrogen receptor alpha (ERalpha), serotonin transporter (SERT), and D2 dopamine receptor (DRD2), were used to explore the individual therapeutic efficacy in the form of docking score using the PyRx 0.8-AutoDock 4.2 platform. According to the docking score (kcal/mol.), BH_P19, BH_P20, BH_P30, BH_P18/BH_P31, and BH_P17 are promising ones. Further, the drug-likeness profiles and ligand stability with AChE for 100 nanoseconds in the molecular dynamics simulation study revealed that BH_P19 was the lead therapeutic candidate among all. Overall, the integration of spectral techniques and computational investigations together highlights and encourages the exploration of natural regimens for AD.