2D-QSAR and 3D-QSAR Analyses for EGFR Inhibitors.

Manman Zhao,Chun Qiu,Bing Niu,Yuhui Zhang,Mengying Zhang,Linfeng Zheng,Dongshu Du,Lin Wang

doi:10.1155/2017/4649191

Abstract

Epidermal growth factor receptor (EGFR) is an important target for cancer therapy. In this study, EGFR inhibitors were investigated to build a two-dimensional quantitative structure-activity relationship (2D-QSAR) model and a three-dimensional quantitative structure-activity relationship (3D-QSAR) model. In the 2D-QSAR model, the support vector machine (SVM) classifier combined with the feature selection method was applied to predict whether a compound was an EGFR inhibitor. As a result, the prediction accuracy of the 2D-QSAR model was 98.99% by using tenfold cross-validation test and 97.67% by using independent set test. Then, in the 3D-QSAR model, the model with q2 = 0.565 (cross-validated correlation coefficient) and r2 = 0.888 (non-cross-validated correlation coefficient) was built to predict the activity of EGFR inhibitors. The mean absolute error (MAE) of the training set and test set was 0.308 log units and 0.526 log units, respectively. In addition, molecular docking was also employed to investigate the interaction between EGFR inhibitors and EGFR.

Highlights

Epidermal growth factor receptor (EGFR), a transmembrane glycoprotein, is classified to the prototype of receptor tyrosine kinases (TKs) family that includes EGFR, ErbB-2, ErbB-3, and ErbB-4
Sensitivity analysis was applied to these nine descriptors to evaluate how they affected the activity of EGFR inhibitors
We considered that the Thr766 and Met769 played a crucial role in the EGFR activity

Summary

Introduction

Epidermal growth factor receptor (EGFR), a transmembrane glycoprotein, is classified to the prototype of receptor tyrosine kinases (TKs) family that includes EGFR, ErbB-2, ErbB-3, and ErbB-4. Several signal transduction cascades are initiated when EGFR is activated and lead to DNA synthesis and cell proliferation [2, 3]. While EGFR is amplified or mutated, DNA synthesis and cell proliferation will be abnormal and lead to cancer. The amplification or mutation of EGFR has been found in human solid tumors, such as glioma, lung cancer, ovarian cancer, and breast cancer. Many EGFR inhibitors have been developed and approved by the FDA, such as lapatinib, which has been applied for the treatment of breast cancer [9]. Other EGFR inhibitors like temozolomide, lomustine, erlotinib, and gefitinib, are approved by the FDA for the treatment of glioma [10, 11]. It is necessary to design and synthesize new potential EGFR inhibitors

Methods

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Discussion

Conclusion