QSAR aided design of potent c‐Met inhibitors using molecular docking, molecular dynamics simulation and binding free energy calculation

Abstract The mesenchymal‐epithelial transition factor (c‐Met) is a tyrosine kinase receptor protein, and excessive cell transformation can lead to cancer. Therefore, there is an urgent need to develop novel receptor tyrosine kinase inhibitors by inhibiting the activity of c‐Met protein. In this study, 41 compounds are selected from the reported literature, and the interactions between phenoxy pyridine derivatives and tumor‐associated proteins are systematically investigated using a series of computer‐assisted drug design (CADD) methods, aiming to predict potential c‐Met inhibitors with high activity. The Topomer CoMFA (q 2 =0.620, R 2 =0.837) and HQSAR (q 2 =0.684, R 2 =0.877) models demonstrate a high level of robustness. Further internal and external validation assessments show high applicability and accuracy. Based on the results of the Topomer CoMFA model, structural fragments with higher contribution values are identified and randomly combined using a fragment splice technique, result in a total of 20 compounds with predicted activities higher than the template molecules. Molecular docking results show that these compounds have good interactions and van der Waals forces with the target proteins. The results of molecular dynamics and ADMET predictions indicate that compounds Y4, Y5, and Y14 have potential as c‐Met inhibitors. Among them, compound Y14 exhibits superior stability with a binding free energy of −165.18 KJ/mol. These studies provide a reference for the future design and development of novel compounds with c‐Met inhibitory activity.