Pharmaceuticals
Targeting Cholinergic Dysfunction and Gingipain Activity in Alzheimer’s Disease: A Dual AChE–Kgp Computational Study
By Ahmad M Sait and Philip J. Day.
Abstract
Introduction
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder for which single-target strategies may be insufficient. This study explored a host–microbial multitarget strategy using a CNS-oriented small molecule predicted to engage both human acetylcholinesterase (AChE) and Porphyromonas gingivalis lysine-specific gingipain K (Kgp).
Methods
A CNS-focused library of 116,226 compounds was standardized and filtered to 1000 candidates for sequential AChE/Kgp docking. Refined docking, interaction-guided pose analysis, dual-target ranking, and SwissADME predictions were used for prioritization. ADKGP_0026671 was subsequently evaluated in single 100 ns molecular dynamics trajectories for AChE and Kgp, alongside donepezil and KYT-36 reference complexes, followed by MM/PBSA endpoint energy analysis.