Unveiling novel VEGFR-2 inhibitors: QSAR modeling, molecular docking, MD and MM-GBSA calculations, pharmacokinetics profiling and DFT studies

Breast cancer ranks as the primary recurring cancer affecting women, the staggering 1.3 million cases reported annually call for impactful intervention strategies. Novel benzoxazole/benzimidazole molecules as VEGFR-2 target inhibitors were unveiled. To achieve this, a reliable QSAR model was built with statistical parameters such as an R² = 0.929, R² adj = 0.917, Q² cv = 0.899, and R² pred = 0.603. Virtual screening identified compound 35 (pIC 50 = 4.165) as a lead molecule which facilitate the design of five novel candidates with higher predicted pIC 50 within the range of 4.208 to 4.698, via the addition and substitution of electron rich –OH, -NH 2 , and -F at strategic positions on the template. Docking simulation with the VEGFR-2 target revealed their excellent affinities from -169.129 to -176.724 and -143.283 and -150.234 kcal/mol. Compound 35d with scores of -176.724, and -150.234 kcal/mol, underwent a 200-ns comparative MD simulation and MM-GBSA analysis with Sorafenib. The results revealed that 35d has a better propensity of stabilizing the VEGFR-2 target than Sorafenib. In addition, pharmacological profiling validated the drug-like potential of the proposed candidates, demonstrating 0 to 1 breaches of the Lipinski's rules and promising ADMET features. DFT analyses illustrates the reactive profiles of the proposed candidates.