Dual-Site Acetylcholinesterase Inhibition and Multiscale Stability of Fused Quinoline Sulfonamides: A Chemoinformatic GA-MLR and Molecular Dynamics Study

Alzheimer’s disease (AD) represents a escalating global neuropharmacological crisis, with prevalence in high-growth demographic regions such as India projected to exceed 14 million by 2040. This study addresses the urgent need for high-potency, dual-site acetylcholinesterase (AChE) inhibitors through an integrated computational pipeline. Background: We address the failure of mono-target paradigms by designing scaffolds capable of simultaneously anchoring the Catalytic Active Site (CAS) and the Peripheral Anionic Site (PAS). Methods: A robust GA-MLR QSAR model was developed from 115 quinoline analogues using 11,135 descriptors. Lead candidates were prioritized via blind molecular docking (7XN1) and 100-ns molecular dynamics (MD) simulations. Results: The five-descriptor model (R2 = 0.7569, QLOO2 = 0.7244) was validated by an external set of 8 experimental compounds (Rext2 = 0.8620). Lead Compound 19 emerged as a superior candidate (ΔG = -11.1 kcal/mol), exhibiting a stable MD trajectory (PL-RMSD ≈ 2.4 Å) and preserving essential Gly121-His447 catalytic anti-correlations. Conclusions: This study provides a statistically validated scaffold and mechanistic foundation for future biomimetic chromatography validation, advancing the high-throughput screening of neuroprotective agents on a global scale.