Towards predictive inhibitor design for the EGFR autophosphorylation activity

Inhibition of the epidermal growth factor receptor (EGFR) tyrosine kinase is one among the pivotal targets for the treatment of cancer. The structural investigation directly halting the EGFR autophosphorylation is expected to give insights into alternatively blocking the aberrant activity of EGFR. The three-dimensional quantitative structure–activity relationship (3D-QSAR) models were developed from the systematic search conformer-based alignment method. Models derived from the training set of 95 compounds showed superior CoMFA as compared with CoMSIA (CoMFA: q2 = 0.50, r2 = 0.74, N = 5, F = 48.83, r2pred = 0.56 while CoMSIA: q2 = 0.48, r2 = 0.62, N = 2, F = 72.70, r2pred = 0.51). Validation of the models by test set prediction of 26 compounds was in good agreement with the experimental results. Further validation by molecular docking superimposition into the 3D-QSAR contour maps was found in agreement with each other. We identified that the structural modification of compound 19 by attachment of a bulky group on pyrrole ring along with an electronegative group on quinazoline ring and a hydrogen-bond donor on methyl formate opens a new avenue towards the optimization of novel chemical entities to develop potent inhibitors for EGFR autophosphorylation.

Graphical abstractIn this study, a new alternative route is presented to control the aberrant EGFR by blocking the autophosphorylation activity. We identified using 3D-QSAR studies that the attachment of a bulky group on C-ring along with an electronegative group on B-ring and a hydrogen-bond donor on methyl formate opens a new avenue towards the optimization of novel chemical entities to develop potent inhibitors for EGFR autophosphorylation. The predictive power of this model stems from good validations obtained by predictive r2 and complementary docking.Figure optionsDownload full-size imageDownload as PowerPoint slide