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

Abdizadeh, Rahman and Hadizadeh, Farzin and Abdizadeh, Tooba (2019) Molecular Modeling Studies of Anti-Alzheimer Agents by QSAR, Molecular Docking and Molecular Dynamic Simulations Techniques. Medicinal Chemistry, 15. ISSN 15734064

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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;〖 r〗_ncv^2, 0.901; 〖 r〗_pred^2, 0.773), CoMFA-RF (q2, 0.629;〖 r〗_ncv^2, 0.901; 〖 r〗_pred^2, 0.824), CoMSIA (q2, 0.754;〖 r〗_ncv^2, 0.919; 〖 r〗_pred^2, 0.874) and HQSAR models (q2, 0.622;〖 r〗_ncv^2, 0.949; 〖 r〗_pred^2, 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. Keywords: Alzheimer`s disease; CoMFA; CoMSIA; HQSAR; molecular docking; pyrimidinylthiourea derivatives.

Item Type: Article
Subjects: WL Nervous system
Divisions: Faculty of Medicine > Basic Sciences Academic Groups > Department of Parasitology and Mycology
Depositing User: zeynab . bagheri
Date Deposited: 20 Jun 2020 06:52
Last Modified: 20 Jun 2020 06:52

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