Molecular Modeling Studies of Anti-Alzheimer Agents by QSAR, Molecular Docking and Molecular Dynamics Simulations Techniques,Medicinal Chemistry

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Molecular Modeling Studies of Anti-Alzheimer Agents by QSAR, Molecular Docking and Molecular Dynamics Simulations Techniques
Medicinal Chemistry ( IF 1.9 ) Pub Date : 2020-10-31 , DOI: 10.2174/1573406415666190806155619
Rahman Abdizadeh ₁ , Farzin Hadizadeh ₂ , Tooba Abdizadeh ₃

Affiliation

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 dynamics simulations were performed on a series of AChE inhibitors to get more potent anti-Alzheimer drugs.

Methods: 2D/3D-QSAR models including CoMFA, CoMFA-RF, CoMSIA, and HQSAR methods were carried out on 40 pyrimidinylthiourea derivatives as data set by the Sybylx1.2 program. Molecular docking and molecular dynamics simulations 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, 0.629; r²_ncv, 0.901; r²_pred, 0.773), CoMFA-RF (q², 0.775; r²_ncv, 0.910; r²_pred, 0.824), CoMSIA (q², 0.754; r²_ncv, 0.919; r²_pred, 0.874) and HQSAR models (q², 0.823; r²_ncv, 0.976; r²_pred, 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 dynamics simulationassisted molecular docking study. The resulted QSAR models could be useful for the rational design of novel potent AChE inhibitors in Alzheimer's treatment.

中文翻译：

通过QSAR，分子对接和分子动力学模拟技术研究抗阿尔茨海默病药物的分子模型

背景：乙酰胆碱酯酶（AChE）是一种丝氨酸水解酶，是治疗阿尔茨海默氏病（AD）的重要药物靶标。因此，新型AChE抑制剂被设计和开发为潜在的候选药物，用于AD的显着治疗。

目的：在这项工作中，对一系列AChE抑制剂进行了包括CoMFA，CoMFA-RF，CoMSIA，HQSAR在内的分子建模研究以及分子对接和分子动力学模拟，以获得更有效的抗阿尔茨海默病药物。

方法：以Sybylx1.2程序为数据集，对40种嘧啶基硫脲衍生物进行了包括CoMFA，CoMFA-RF，CoMSIA和HQSAR方法在内的2D / 3D-QSAR模型。分别使用MOE软件和Sybyl程序进行了分子对接和分子动力学模拟。偏最小二乘（PLS）模型作为描述符用于QSAR模型生成。

结果：的CoMFA（Q ²，0.629; R ²_NCV，0.901; R ²_预解码值，0.773），的CoMFA-RF（Q ²，0.775; R ²_NCV，0.910; R ²_预解码值，0.824），指数分析（Q ²， 0.754； r ²_ncv为0.919； r ²_pred为0.874）和用于训练和测试集的HQSAR模型（q ^2为0.823； r ²_ncv为0.976； r ²_pred为0.854）产生了显着的统计结果。