Quinoxaline derivatives in identifying novel VEGFR-2 inhibitors: A combined 3D-QSAR, molecular docking and molecular...

Vascular endothelial growth factor receptor 2 (VEGFR-2) is a key target for cancer treatment. VEGFR-2 inhibitors, which would initiate apoptosis, have been identified. To derive novel and potent VEGFR-2 inhibitors, a series of quinoxaline derivatives were studied using a combination of molecular modeling approaches, including three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and molecular dynamics (MD) simulations. We developed robust 3D-QSAR models (CoMFA: R²_cv = 0.663, R²_pred = 0.6126; CoMSIA: R²_cv = 0.631, R²_pred = 0.6974) that reveal the structural determinants for VEGFR-2 inhibition. These models were validated for the reliability and predictability. Contour maps provided insights into the requirements for substituents on the common substructure. Molecular docking was conducted to validate the developed models and provided initial conformation for following MD simulations. MD simulations identified vital amino acid residues (Leu838、Phe916、Leu976) involved in ligand-receptor interactions. This workflow can be applied to optimize and design novel and potent VEGFR-2 inhibitors.