Designing novel potent oxindole derivatives as VEGFR2 inhibitors for cancer therapy: Computational insights from molecular docking, drug-likeness, DFT, and structural dynamics studies

Abstract

Oxindole is a γ-lactam featuring a heterocyclic core, combining pyrrole and benzene rings with a carbonyl group at the second position. This scaffold is present in numerous bioactive compounds, both natural and synthetic, and has emerged as a privileged pharmacophore in medicinal chemistry due to its broad biological activity. Substitution at the 3-position of the 2-oxindole structure has been shown to enhance potency and selectivity, especially in anticancer drug development. Breast cancer, a prevalent and challenging disease affecting millions of women worldwide, underscores an urgent need for more effective treatments. Current therapies often exhibit limited efficacy, significant side effects, and resistance issues, highlighting the demand for novel drugs with improved safety profiles. This study focuses on vascular endothelial growth factor receptor-2 (VEGFR-2), an essential regulator of tumor angiogenesis, as a potential target for breast cancer therapy. Through molecular docking-based virtual screening of 360 designed oxindole derivatives, three compounds (BIATAM, CIHTAM, and IATAM) were identified as potential candidates, each demonstrating high docking scores (>7 kcal/mol) and favorable interactions, including hydrogen bonding, hydrophobic contacts, and stacking. Among these, BIATAM emerged as the lead compound due to its superior docking performance, favorable pharmacokinetic profiles, and compliance with Lipinski's Rule of Five. Density functional theory (DFT) calculations confirmed its chemical stability, while molecular dynamics simulations (MDS) revealed high structural stability. Principal component-based free energy landscape (FEL) analysis highlighted limited conformational flexibility, and MM/PBSA-based binding energy calculations reinforced its strong affinity within the VEGFR-2 binding pocket. These comprehensive computational findings suggest that BIATAM holds promising potential as a novel therapeutic option for treating breast cancer.