Molecular Docking Analysis of Novel Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment

Document Type : Original Article

Authors

1 Department of Cell and Molecular Biology , Go.C, Islamic Azad University, Gorgan, Iran.

2 Department of Genetics, Faculty of Advanced Science and Technology, TeMS.C, Islamic Azad University, Tehran, Iran.

10.22038/psj.2025.92090.1501

Abstract

Introduction: 
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive decline. One therapeutic strategy involves inhibiting acetylcholinesterase (AChE), the enzyme responsible for acetylcholine degradation in synaptic clefts. AChE inhibitors enhance cholinergic neurotransmission, thereby alleviating cognitive symptoms associated with AD. This study aimed to identify and evaluate novel AChE inhibitors structurally related to rivastigmine using computational techniques, including virtual screening and molecular docking, to discover potential lead compounds for AD therapy.
 Materials and Methods: 
The crystal structure of AChE (PDB ID: 6M0E) was obtained from the Protein Data Bank. Ligands with over 95% structural similarity to rivastigmine, based on the Tanimoto coefficient, were retrieved from PubChem. The ligands were energy-minimized and screened virtually using PyRx. Molecular docking was performed with AutoDock 4.2, and docking results were analyzed in terms of binding energy, inhibition constant (Ki), and interaction profiles to assess inhibitory potential.
Results: 
Among the screened compounds, Ligand 13 exhibited the most favorable binding affinity, with a binding energy of –5.07 kcal/mol and an inhibition constant of 192.84 µM. Interaction analysis revealed that Ligand 13 formed three hydrogen bonds with key residues Ser215 and Arg177 in the AChE active site, suggesting stronger binding than rivastigmine.
Conclusion:
 Ligand 13 emerged as a promising AChE inhibitor candidate for AD treatment. Further studies involving pharmacokinetic, toxicity, and experimental validation are necessary to confirm its therapeutic potential.

Keywords

Main Subjects

References

  1. Kamatham PT, Shukla R, Khatri DK, Vora LK. Pathogenesis, diagnostics, and therapeutics for Alzheimer's disease: Breaking the memory barrier. Ageing Research Reviews. 2024; 101:102481.
  2. Knopman DS, Amieva H, Petersen RC, Chételat G, Holtzman DM, Hyman BT, Nixon RA, Jones DT. Alzheimer disease. Nature reviews Disease primers. 2021;7(1):33.
  3. Castellani RJ, Rolston RK, Smith MA. Alzheimer disease. Disease-a-month: DM. 2010; 56(9):484.
  4. Peitzika SC, Pontiki E. A review on recent approaches on molecular docking studies of novel compounds targeting acetylcholinesterase in Alzheimer disease. Molecules. 2023 Jan 21; 28(3):1084.
  5. Dighe SN, De la Mora E, Chan S, Kantham S, McColl G, Miles JA, Veliyath SK, Sreenivas BY, Nassar ZD, Silman I, Sussman JL. Rivastigmine and metabolite analogues with putative Alzheimer’s disease-modifying properties in a Caenorhabditis elegans model. Communications Chemistry. 2019;2(1):35.
  6. Gottwald MD, Rozanski RI. Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer’s disease: review and current status. Expert opinion on investigational drugs. 1999;8(10):1673-82.
  7. Zhang J, Zhang Y, Wang J, Xia Y, Zhang J, Chen L. Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies. Signal transduction and targeted therapy. 2024;9(1):211.
  8. Thai QM, Pham TN, Hiep DM, Pham MQ, Tran PT, Nguyen TH, Ngo ST. Searching for AChE inhibitors from natural compounds by using machine learning and atomistic simulations. Journal of Molecular Graphics and Modelling. 2022; 115:108230.
  9. Jang C, Yadav DK, Subedi L, Venkatesan R, Venkanna A, Afzal S, Lee E, Yoo J, Ji E, Kim SY, Kim MH. Identification of novel acetylcholinesterase inhibitors designed by pharmacophore-based virtual screening, molecular docking and bioassay. Scientific reports. 2018;8(1):14921.
  10. Mahmood Janlou MA, Sahebjamee H, Yazdani M, Fozouni L. Structure-based virtual screening and molecular dynamics approaches to identify new inhibitors of Staphylococcus aureus sortase A. Journal of Biomolecular Structure and Dynamics. 2024;42(3):1157-69.
  11. Allouche AR. Gabedit—A graphical user interface for computational chemistry softwares. Journal of computational chemistry. 2011; 32(1): 174-82.
  12. Uba AI, Yelekçi K. Carboxylic acid derivatives display potential selectivity for human histone deacetylase 6: Structure-based virtual screening, molecular docking and dynamics simulation studies. Computational Biology and Chemistry. 2018; 75:131-42.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  1. Walczak-Nowicka ŁJ, Herbet M. Acetylcholinesterase inhibitors in the treatment of neurodegenerative diseases and the role of acetylcholinesterase in their pathogenesis. International journal of molecular sciences. 2021; 22(17):9290.
  2. Thawabteh AM, Ghanem AW, AbuMadi S, Thaher D, Jaghama W, Karaman D, Karaman R. Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease. Molecules. 2024; 29(21):5131.
  3. Li Q, Yang H, Chen Y, Sun H. Recent progress in the identification of selective butyrylcholinesterase inhibitors for Alzheimer's disease. European journal of medicinal chemistry. 2017; 132:294-309.
  4. Thandivel S, Rajan P, Gunasekar T, Arjunan A, Khute S, Kareti SR, Paranthaman S. In silico molecular docking and dynamic simulation of anti-cholinesterase compounds from the extract of Catunaregam spinosa for possible treatment of Alzheimer's disease. Heliyon. 2024;10(7).
  5. Martins MM, Branco PS, Ferreira LM. Enhancing the therapeutic effect in Alzheimer's disease drugs: The role of Polypharmacology and Cholinesterase inhibitors. ChemistrySelect. 2023;8(10):e202300461.
  6. Alshamari AK, Hassan NA, Alshammari OA, Basiony EA, Alshammari MZ, Hassan AA. Synthesis, Biological Evaluation, Molecular Docking, Molecular Dynamics, and ADME Studies of Novel Thiouracil Derivatives as Dual Inhibitors of Butyrylcholinesterase and Acetylcholinesterase Enzymes. Journal of Molecular Structure. 2024:141154.
Journal of Patient Safety & Quality Improvement
Volume 14, Issue 1
January 2026
Pages 11-18

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