Multiscale Computational Prioritization of Chromone-Based Acetylcholinesterase Ligands

Identifying acetylcholinesterase (AChE) ligands for Alzheimer’s disease research requires integrating molecular recognition with pharmacokinetic and safety considerations. Here, four designed chromone derivatives (M1–M4) were investigated to determine how conformational sampling and complementary molecular descriptors refine docking-based prioritization. Donepezil redocking in human AChE and cross-docking into Torpedo californica AChE recovered the crystallographic and transferred reference orientations, respectively, with RMSDs of 0.942 and 1.074 Å. Molecular docking was integrated with 800 ns molecular dynamics, MM/PBSA, electronic-structure calculations, and pharmacokinetic/toxicity predictions. M4 achieved the most favorable chromone docking score (−9.6 kcal mol−1), whereas M3 yielded the most favorable chromone MM/PBSA estimate within the 775–800 ns window (−23.90 ± 2.31 kcal mol−1). Donepezil retained a more favorable MM/PBSA estimate (−41.00 ± 2.75 kcal mol−1). M4 exhibited the highest electronic hardness, while predicted toxicity profiles revealed distinct liabilities across the series. The divergence between docking and sampled energetics highlights the value of integrating complementary criteria when selecting compounds for experimental evaluation. These protocol-dependent findings prioritize M3 and M4 as complementary computational candidates requiring experimental confirmation of AChE inhibition, selectivity, and safety.