3D QSAR Studies on a Series of 4-Anilino Quinazoline Derivatives as Tyrosine Kinase (EGFR) Inhibitor: The k-Nearest Neighbor Molecular Field Analysis Approach

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Epidermal growth factor receptor (EGFR) protein tyrosine kinases (PTKs) are known for its role in cancer. Quinazoline have been reported to be the molecules of interest, with potent anticancer activity and they act by binding to ATP site of protein kinases. ATP binding site of protein kinases provides an extensive opportunity to design newer analogs. With this background, we report an attempt to discern the structural and physicochemical requirements for inhibition of EGFR tyrosine kinase. The k-Nearest Neighbor Molecular Field Analysis (kNN-MFA), a three dimensional quantitative structure activity relationship (3D- QSAR) method has been used in the present case to study the correlation between the molecular properties and the tyrosine kinase (EGFR) inhibitory activities on a series of quinazoline derivatives using SW, SA and GA variable selection method. kNN-MFA calculations for both electrostatic and steric field were carried out. The master grid maps derived from the best model has been used to display the contribution of electrostatic potential and steric field. The statistical results by SW variable selection method has shown significant correlation coefficient r2 (q2) of 0.9141, r2 for external test set (pred_r2) 0.8033, coefficient of correlation of predicted data set (pred_r2se) of 0.7845, and k nearest neighbor of 2.Therefore, this study not only casts light on binding mechanism between EGFR and its inhibitors, but also provides hints for the design of new EGFR inhibitors with observable structural diversity.