A novel thieno[2,3-d]pyrimidine derivative inhibiting vascular endothelial growth factor receptor-2: A story of computer-aided drug discovery

Abstract

Following the pharmacophoric features of vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors, a novel thieno[2,3-d]pyrimidine derivative has been designed and its activity against VEGFR-2 has been demonstrated by molecular docking studies that showed an accurate binding mode and an excellent binding energy. Furthermore, the recorded binding was confirmed by a series of molecular dynamics simulation studies, which also revealed precise energetic, conformational, and dynamic changes. Additionally, molecular mechanics with generalized Born and surface area solvation and polymer-induced liquid precursors studies were conducted and verified the results of the MD simulations. Next, in silico absorption, distribution, metabolism, excretion, and toxicity studies have also been conducted to examine the general drug-like nature of the designed candidate. According to the previous results, the thieno[2,3-d]pyrimidine derivative was synthesized. Fascinatingly, it inhibited VEGFR-2 (IC₅₀ = 68.13 nM) and demonstrated strong inhibitory activity toward human liver (HepG2), and prostate (PC3) cell lines with IC₅₀ values of 6.60 and 11.25 µM, respectively. As well, it was safe and showed a high selectivity index against normal cell lines (WI-38). Finally, the thieno[2,3-d]pyrimidine derivative arrested the growth of the HepG2 cells at the G2/M phase inducing both early and late apoptosis. These results were further confirmed through the ability of the thieno[2,3-d]pyrimidine derivative to induce significant changes in the apoptotic genes levels of caspase-3, caspase-9, Bcl-2 associated X-protein, and B-cell lymphoma 2.

Keywords: CADD; MD simulations; VEGFR-2 inhibitors; apoptosis; docking; thieno[2,3-d]pyrimidine.