Abstract / Summary
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. Results: ADKGP_0026671 showed docking scores of −11.804 kcal/mol for AChE and −7.345 kcal/mol for Kgp, was predicted to be BBB-permeant and not a P-glycoprotein substrate, and contained no PAINS or Brenk alerts. The single MD trajectories showed continued binding-site association and limited protein backbone deviation over the simulated period, although reproducibility cannot be established without independent replicas. MM/PBSA endpoint estimates were negative for AChE (−18.86 kcal/mol) and Kgp (−15.67 kcal/mol), but less favorable than donepezil and KYT-36, respectively. Conclusions: ADKGP_0026671 showed a balanced computational profile across two mechanistically distinct targets, supporting experimental evaluation of a host–microbial dual-target strategy in AD. These findings remain hypothesis-generating and require biochemical validation and replicated simulations.