Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies. (31st December 2022)

• Record Type: Journal Article
• Authors: Yousef, Reda G.; Ibrahim, Albaraa; Khalifa, Mohamed M.; Eldehna, Wagdy M.; Gobaara, Ibraheem M. M.; Mehany, Ahmed B. M.; Elkaeed, Eslam B.; Alsfouk, Aisha A.; Metwaly, Ahmed M.; Eissa, Ibrahim H.
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 37:Number 1(2022)
• Page Start: 1389
• Page End: 1403
• Publication Date: 2022-12-31
• Subjects: Apoptosis -- anticancer -- immunomodulatory -- VEGFR-2 inhibitors -- molecular dynamic simulation; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2022.2070744
• Languages: English
• ISSNs: 1475-6366

Abstract

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.