Integrated spectroscopic,DFT,molecular docking,and dynamics analysis of 3-(1,3-benzodioxol-5-yl)-1-phenyl-2-propen-1-one as an AChE inhibitor

Abstract

The molecular structure of 3-(1,3-benzodioxol-5-yl)-1-phenyl-2-propen-1-one (3BPO), a flavonoid derivative with potential neuroprotective properties against Alzheimer's disease (AD), was comprehensively investigated using XRD, FT-IR, FT-Raman, and UV–Vis spectroscopy, complemented by DFT calculations at the B3LYP/6-311++G(d,p) level. The computed HOMO–LUMO energy gap 3.65 eV in the gas phase and 3.45 eV in DMSO suggests a balance between electronic stability and chemical reactivity. Molecular electrostatic potential (MEP) mapping, Mulliken charge analysis, and topological descriptors, including ELF, LOL, and RDG, provided detailed insights into electron distribution patterns and intramolecular interactions. Hirshfeld surface and fingerprint analyses further clarified the contributions of intra- and intermolecular contacts to the crystal packing. Molecular docking studies against six AChE targets revealed strong binding affinities, with the highest interaction energy of 10.4 kcal mol⁻¹. Key hydrogen-bonding and π–π stacking interactions supported the stable ligand–protein complexes, indicating a binding efficiency comparable to that of the standard drug donepezil.Subsequent 100 ns molecular dynamics simulations confirmed the stability of the 3BPO-AChE complexes, as evidenced by favourable RMSD, RMSF, radius of gyration, and SASA trends. ADMET and SwissADME predictions further indicated excellent drug-likeness, efficient blood-brain barrier penetration, and an improved safety profile compared to donepezil. Collectively, these results position 3BPO as a promising multi-target lead candidate for further development in Alzheimer's disease therapeutics.