Computational and Spectroscopic Insights Into 4‐Methoxychalcone as a Potential Acetylcholinesterase Inhibitor: A DFT and Molecular Docking Approach

ABSTRACT 4‐Methoxychalcone (4MC) is investigated for its potential as an acetylcholinesterase (AChE) inhibitor to treat Alzheimer's disease (AD). We investigated the electrical, vibrational, and structural properties of 4MC with computational and spectroscopic methods. In order to improve the molecular geometry, investigate the stability and reactivity of the chemical in both gas and DMSO phases, density functional theory (DFT) was performed using the B3LYP/6‐311++G(d,p) basis set. Potential energy surface (PES) analysis identified the most stable conformer. Experimental methods such as FT‐Raman, FT‐IR, x‐ray diffraction (XRD), UV–Vis, and NMR spectroscopy were employed to verify the computational predictions. Comparing the measured UV–visible spectra with the theoretical time‐dependent DFT‐calculated spectra is a good instance. Analysis of the molecule's reactivity and electron transfer behavior was done by looking at its frontier molecular orbitals. In the gas phase, a HOMO‐LUMO energy gap of ∼3.84 eV suggests relatively high chemical reactivity, which could contribute to potential bioactivity. Intermolecular interactions and charge transfer properties were revealed by the investigations of Hirshfeld surface, Mulliken charge, natural bond orbital (NBO), and molecular electrostatic potential (MEP). The wave function‐based topology investigations, including localized orbital locator (LOL), electron localization function (ELF), Reduced Density Gradient (RDG), and non‐covalent interaction (NCI) characteristics, have been extensively studied. Molecular docking revealed a strong binding affinity of 4MC (−9.8 kcal/mol) with AChE, comparable to that of the standard drug donepezil. Molecular dynamic (MD) simulations confirmed complex stability through root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration ( R g ). Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) results showed favorable pharmacokinetics with good BBB permeability, high intestinal absorption, and low toxicity, supporting 4MC's potential as a candidate for Alzheimer's therapy.