New thiazolidine-2,4-diones as effective anti-proliferative and anti-VEGFR-2 agents: Design, synthesis, in vitro, docking, MD simulations, DFT, ADMET, and toxicity studies

• Published in: Computational biology and chemistry 2023-12, Vol.107, p.107958-107958, Article 107958
• Main Authors: Elkady, Hazem, Abuelkhir, Abdelrahman A., Rashed, Mahmoud, Taghour, Mohammed S., Dahab, Mohammed A., Mahdy, Hazem A., Elwan, Alaa, Al-ghulikah, Hanan A., Elkaeed, Eslam B., Ibrahim, Ibrahim M., Husein, Dalal Z., Metwaly, Ahmed, Eissa, Ibrahim H.
• Format: Article
• Language: English
• Subjects: Anti-proliferative; Antineoplastic Agents - pharmacology; Apoptosis; Cell Proliferation; DFT; Docking; Drug Design; Drug Screening Assays, Antitumor; MD simulations; Molecular Docking Simulation; Molecular Structure; Phosphorylation; Protein Kinase Inhibitors; Structure-Activity Relationship; Thiazolidine-2,4-dione; Thiazolidines - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; VEGFR-2
• ISSN: 1476-9271; 1476-928X
• DOI: 10.1016/j.compbiolchem.2023.107958

Novel thiazolidine-2,4-dione derivatives, 11a-g, were designed, and synthesized targeting the VEGFR-2 protein. The in vitro studies indicated the abilities of the synthesized derivatives to inhibit VEGFR-2 and prevent the growth of two different cancer cell types, HepG2 and MCF-7. Compound 11 f exhibited the strongest anti-VEGFR-2 activity (IC50 = 0.053 µM). As well, compound 11 f showed impressive anti-proliferative activity against the mentioned cancer cell lines with IC50 values of 0.64 ± 0.01 and 0.53 ± 0.04 µM, respectively. Additionally, compound 11 f arrested the MCF-7 cell cycle at the S phase and increased the overall apoptosis percentage. Furthermore, cell migration assay revealed that compound 11 f has a significant ability to prevent migration and healing potentialities of MCF-7. Moreover, computational studies were used to conduct the molecular investigation of the VEGFR-2-11 f complex. The kinetic and structural features of the complex were examined using molecular dynamics simulations and molecular docking. Besides, Principal component analysis (PCA) was used to explain the dynamics of the VEGFR-2-11 f complex at various spatial scales. The DFT calculations also provided further clarity regarding compound 11 f's structural and electronic features. To evaluate how closely the developed compounds might look like drugs, ADMET and toxicity experiments were computed. To conclude, the presented study demonstrates the potential of compound 11 f as a viable anti-cancer drug, which can serve as a prototype for future structural modifications and further biological investigations. [Display omitted] •Novel thiazolidine-2,4-dione derivatives were designed and synthesized as VEGFR-2 inhibitors.•In vitro cytotoxic activities against MCF-7 and HepG2 cell lines and VEGFR-2 inhibitory activities were evaluated.•The most promising member was subjected for further mechanistic studies including apoptosis and cell cycle assay.•In silico studies including molecular docking, MD simulation, DFT, ADMET, and toxicity studies were carried out.