The use of machine learning modeling, virtual screening, molecular docking, and molecular dynamics simulations to identify potential VEGFR2 kinase inhibitors

Targeting the signaling pathway of the Vascular endothelial growth factor receptor-2 is a promising approach that has drawn attention in the quest to develop novel anti-cancer drugs and cardiovascular disease treatments. We construct a screening pipeline using machine learning classification integrated with similarity checks of approved drugs to find new inhibitors. The statistical metrics reveal that the random forest approach has slightly better performance. By further similarity screening against several approved drugs, two candidates are selected. Analysis of absorption, distribution, metabolism, excretion, and toxicity, along with molecular docking and dynamics are performed for the two candidates with regorafenib as a reference. The binding energies of molecule1, molecule2, and regorafenib are − 89.1, − 95.3, and − 87.4 (kJ/mol), respectively which suggest candidate compounds have strong binding to the target. Meanwhile, the median lethal dose and maximum tolerated dose for regorafenib, molecule1, and molecule2 are predicted to be 800, 1600, and 393 mg/kg, and 0.257, 0.527, and 0.428 log mg/kg/day, respectively. Also, the inhibitory activity of these compounds is predicted to be 7.23 and 7.31, which is comparable with the activity of pazopanib and sorafenib drugs. In light of these findings, the two compounds could be further investigated as potential candidates for anti-angiogenesis therapy.