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

doi:10.1080/14756366.2022.2070744

Back

Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies

Journal article

Open access

Peer reviewed

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 and Ibrahim H Eissa

Journal of enzyme inhibition and medicinal chemistry, Vol.37(1), pp.1389-1403

12/2022

DOI: https://doi.org/10.1080/14756366.2022.2070744

PMID: 35577416

Abstract

Antineoplastic Agents - metabolism

Antineoplastic Agents - pharmacology

Cell Proliferation

Drug Screening Assays, Antitumor

Humans

Interleukin-6

Molecular Docking Simulation

Molecular Dynamics Simulation

Molecular Structure

Protein Kinase Inhibitors - metabolism

Protein Kinase Inhibitors - pharmacology

Structure-Activity Relationship

Tumor Necrosis Factor-alpha

Vascular Endothelial Growth Factor Receptor-2

A library of modified VEGFR-2 inhibitors was designed as VEGFR-2 inhibitors. Virtual screening was conducted for the hypothetical library using docking, ADMET, and toxicity studies. Four compounds exhibited high affinity against VEGFR-2 and an acceptable range of the drug-likeness. These compounds were synthesised and subjected to cytotoxicity assay against two cancer cell lines besides VEGFR-2 inhibitory determination. Compound showed cytotoxic activity against HCT-116 cells almost double that of sorafenib. Compounds , , and showed good IC values against VEGFR-2. Compound markedly increased the levels of caspase-8 and BAX expression and decreased the anti-apoptotic Bcl-2 level. Additionally, compound 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 decreased the level of TNF-α and IL6 and inhibited TNF-α and IL6. MD simulations studies were performed over 100 ns.

Files and links (1)

url

https://doi.org/10.1080/14756366.2022.2070744View

Published (Version of record) Open

Metrics

1 Record Views

Details

Title: Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies
Creators - without role: Reda G Yousef - Al-Azhar University
Albaraa Ibrahim - Al Azhar University
Mohamed M Khalifa - Al Azhar University
Wagdy M Eldehna - Kafrelsheikh University
Ibraheem M M Gobaara - Al Azhar University
Ahmed B M Mehany - Al Azhar University
Eslam B Elkaeed - Alfaisal University
Aisha A Alsfouk - Princess Nourah bint Abdulrahman University
Ahmed M Metwaly - Al Azhar University
Ibrahim H Eissa - Al Azhar University
Publication Details: Journal of enzyme inhibition and medicinal chemistry, Vol.37(1), pp.1389-1403
Identifiers: 9914083808331
Academic Unit: Almaarefa University; Princess Nourah bint Abdulrahman University
Language: English
Resource Type: Journal article