Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies.
J Enzyme Inhib Med Chem
; 37(1): 1389-1403, 2022 Dec.
Article
en En
| MEDLINE
| ID: mdl-35577416
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.
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Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Receptor 2 de Factores de Crecimiento Endotelial Vascular
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Inhibidores de Proteínas Quinasas
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Antineoplásicos
Tipo de estudio:
Diagnostic_studies
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Screening_studies
Límite:
Humans
Idioma:
En
Año:
2022
Tipo del documento:
Article