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Molecular Modeling Studies of Anti-Alzheimer Agents by QSAR, Molecular Docking and Molecular Dynamic Simulations Techniques


Rahman Abdizadeh, Farzin Hadizadeh and Tooba Abdizadeh*   Pages 1 - 25 ( 25 )


Background: Acetylcholinesterase (AChE), a serine hydrolase, is an important drug target in the treatment of Alzheimer's disease (AD). Thus, novel AChE inhibitors were designed and developed as potential drug candidates, for significant therapy of AD.

Objective: In this work, molecular modeling studies, including CoMFA, CoMFA-RF, CoMSIA, HQSAR and molecular docking and molecular dynamic simulations were performed on a series of AChE inhibitors to get more potent anti-Alzheimer drugs.

Methods: The 2D/3D-QSAR models including CoMFA, CoMFA-Rf, CoMSIA, and H-QSAR methods were carried out on 59 pyrimidinylthiourea derivatives as data set by the Sybylx1.2 program. Molecular docking and molecular dynamic simulation were performed using the MOE software and the Sybyl program, respectively. Partial least squares (PLS) model as descriptors was used for QSAR model generation.

Results: The CoMFA (q2, 0.775; 41 r2ncv, 0.901; ri2pred, 0.773), CoMFA-RF (q2, 0.629; r2ncv, 0.901; r2pred, 0.824), CoMSIA (q2, 0.754; r2ncv, 0.919; r2pred, 0.874) and HQSAR models (q2, 0.622; r2ncv, 0.949; r2pred, 0.854) for training and test set yielded significant statistical results.

Conclusion: These QSAR models were excellent, robust and had good predictive capability. Contour maps obtained from the QSAR models were validated by molecular dynamic simulation-assisted molecular docking study. The resulted QSAR models could be useful for rational design of novel potent AChE inhibitors in Alzheimer's treatment.


Alzheimer`s disease, CoMFA, CoMSIA, HQSAR, pyrimidinylthiourea derivatives, molecular docking


Department of Medical Parasitology and Mycology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Clinical Biochemistry Research Center, Basic Health Sciences Institute, Sharekord University of Medical Sciences, Shahrekord

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