Fibroblast growth factor receptor (FGFR) plays a vital role in tissue regeneration, angiogenesis, and embryogenesis. 3D-QSAR and molecular modeling methods are widely used for designing novel compounds for the determination of inhibitory activity against the biological target. In the present study, 3D-QSAR (CoMFA and CoMSIA) analysis was performed on 1, 6-naphthyridines, and pyridopyrimidines as potential FGFR inhibitors as anticancer agents. The best CoMFA and CoMSIA models were generated from test and training set derivatives with leave-one-out correlation coefficients () 0.591 and 0.667, cross-validated correlation coefficients () 0.584 and 0.652, conventional coefficients () 0.978 and 0.975 respectively. The developed models were validated by a test set of 12 compounds providing acceptable predictive correlation coefficient () 0.61 and 0.68 for both models. The generated CoMFA and CoMSIA contour maps could be used to design novel 1, 6-naphthyridine analogs. Molecular docking studies indicated that compound occupied the active site of the FGFR kinase interacting with Glu520 in the catalytic region, Asp630 in the DFG motif, and Met524 in the hinge region which compared with standard drug Ponatinib. The molecular dynamics simulation analysis revealed that the inhibitor displayed binding stability in the active site of the FGFR4 by making two hydrogen bonds and one π-cation interaction. Collectively the outcome of the study suggested that the applications of ligand-based and structure-based approaches could be applied for the design of new FGFR4 inhibitors as anticancer agents.Communicated by Ramaswamy H. Sarma.