#107 Insight into anti-cancer FGFR inhibitors by 3D-QSAR method

Abstract

Fibroblast growth factor receptor (FGFR) plays a vital role in tissue regeneration, angiogenesis, and embryogenesis. 3D QSAR and molecular docking methods are widely used to design new compounds to determine inhibitory activity against the biological target. In the present study, 3D-QSAR (CoMFA and CoMSIA) and molecular docking analysis were performed on 1,6-naphthyridines and pyridopyrimidines as potential FGFR inhibitors anticancer agents. 3D-QSAR was performed employing forty-one molecules from the literature using Sybyl suite, and molecular docking was performed using Glide suite of Schrodinger package. The best CoMFA and CoMSIA models were generated from test and training set derivatives with leave-one-out correlation coefficients (q²) 0.591 and 0.667, cross-validated correlation coefficients (r²cv) 0.584 and 0.652, conventional coefficients (r²ncv) 0.978 and 0.975 respectively. Both the models were validated by a test set of twelve compounds providing acceptable predictive correlation coefficient (r²pred) 0.61 and 0.68 for both models. The generated CoMFA and CoMSIA contour maps were used to design new 1,6-naphthyridines and pyridopyrimidines. Molecular docking studies indicated that compounds 75 and 29 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. Collectively the outcome of the study suggested that the applications of ligand-based and structure-based approaches can be applied to discover new FGFR inhibitors as anticancer agents.