Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies
Reda G. Yousef, Albaraa Ibrahim, Mohamed M. Khalifa, Wagdy M. Eldehna, Ibraheem M. M. Gobaara, Ahmed B. M. Mehany, Eslam B. Elkaeed, Aisha A. Alsfouk, Ahmed M. Metwaly, Ibrahim H. Eissa
Abstract
A library of modified VEGFR-2 inhibitors was designed as VEGFR-2 inhibitors. Virtual screening was conducted for the hypothetical library using in silico docking, ADMET, and toxicity studies. Four compounds exhibited high in silico affinity against VEGFR-2 and an acceptable range of the drug-likeness. These compounds were synthesised and subjected to in vitro cytotoxicity assay against two cancer cell lines besides VEGFR-2 inhibitory determination. Compound D-1 showed cytotoxic activity against HCT-116 cells almost double that of sorafenib. Compounds A-1, C-6, and D-1 showed good IC50 values against VEGFR-2. Compound D-1 markedly increased the levels of caspase-8 and BAX expression and decreased the anti-apoptotic Bcl-2 level. Additionally, compound D-1 caused cell cycle arrest at pre-G1 and G2-M phases in HCT-116 cells and induced apoptosis at both early and late apoptotic stages. Compound D-1 decreased the level of TNF-α and IL6 and inhibited TNF-α and IL6. MD simulations studies were performed over 100 ns.