Targeting Cholinergic Dysfunction and Gingipain Activity in Alzheimer's Disease: A Dual AChE-Kgp Computational Study.
4 affiliations
- 1Medical Laboratory Science, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
- 2Regenerative Medicine Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
- 3Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK.
- 4Department of Medicine, University of Cape Town, Cape Town 7925, South Africa.
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. 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.
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BibTeX
@article{sait2026targeting,
title = {{Targeting Cholinergic Dysfunction and Gingipain Activity in Alzheimer's Disease: A Dual AChE-Kgp Computational Study.}},
author = {Ahmad M Sait and Philip J R Day},
journal = {Pharmaceuticals (Basel, Switzerland)},
year = {2026},
month = oct,
doi = {10.3390/ph19101589},
url = {https://europepmc.org/article/MED/42943286},
note = {CC BY},
}
RIS
TY - JOUR
TI - Targeting Cholinergic Dysfunction and Gingipain Activity in Alzheimer's Disease: A Dual AChE-Kgp Computational Study.
AU - Ahmad M Sait
AU - Philip J R Day
PY - 2026
DA - 2026/10/08
JO - Pharmaceuticals (Basel, Switzerland)
DO - 10.3390/ph19101589
UR - https://europepmc.org/article/MED/42943286
AB - 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.
SN - 1424-8247
ER -