Design, synthesis, anti-proliferative evaluation, docking, and MD simulation studies of new thieno[2,3-d]pyrimidines...

In this work, new thieno[2,3-d]pyrimidine-derived compounds possessing potential anticancer activities were designed and synthesized to target VEGFR-2. The thieno[2,3-d]pyrimidine derivatives were tested in vitro for their abilities to inhibit VEGFR-2 and to prevent cancer cell growth in two types of cancer cells, MCF-7 and HepG2. Compound 18 exhibited the strongest anti-VEGFR-2 potential with an IC₅₀ value of 0.084 μM. Additionally, it displayed excellent proliferative effects against MCF-7 and HepG2 cancer cell lines, with IC₅₀ values of 10.17 μM and 24.47 μM, respectively. Further studies revealed that compound 18 induced cell cycle arrest in G2/M phase and promoted apoptosis in MCF-7 cancer cells. Apoptosis was stimulated by compound 18 by increasing BAX (3.6-fold) and decreasing Bcl-2 (3.1-fold). Additionally, compound 18 significantly raised the levels of caspase-8 (2.6-fold) and caspase-9 (5.4-fold). Computational techniques were also used to investigate the VEGFR-2-18 complex at a molecular level. Molecular docking and molecular dynamics simulations were performed to assess the structural and energetic features of the complex. The protein-ligand interaction profiler analysis identified the 3D interactions and binding conformation of the VEGFR-2-18 complex. Essential dynamics (ED) study utilizing principal component analysis (PCA) described the protein dynamics of the VEGFR-2-18 complex at various spatial scales. Bi-dimensional projection analysis confirmed the proper binding of the VEGFR-2-18 complex. In addition, the DFT studies provided insights into the structural and electronic properties of compound 18. Finally, computational ADMET and toxicity studies were conducted to evaluate the potential of the thieno[2,3-d]pyrimidine derivatives for drug development. The results of the study suggested that compound 18 could be a promising anticancer agent that may provide effective treatment options for cancer patients. Furthermore, the computational techniques used in this research provided valuable insights into the molecular interactions of the VEGFR-2-18 complex, which may guide future drug design efforts. Overall, this study highlights the potential of thieno[2,3-d]pyrimidine derivatives as a new class of anticancer agents and provides a foundation for further research in this area.