Identification of novel Src, Bcl-2 dual inhibitors by the pharmacophore model, molecular docking, and molecular dynamics simulations

Src is a tyrosine kinase that plays a key role in cell proliferation, migration, invasion, and angiogenesis. Bcl-2 is an essential checkpoint for apoptosis, and its overexpression is important for tumor cells to escape apoptosis and further acquire drug resistance. The recent studies have shown that Src and Bcl-2 have synergistic effects in suppressing stem cell-like breast cancer. In this study, Src and Bcl-2 dual-target inhibitors were identified by computer-aided drug design. Six million molecules were screened by the pharmacophore model and molecular docking. Finally, 175 compounds were obtained. Based on the studies of Src and Bcl-2 inhibitors, the structural modification of the first ranked compound obtained QST101. Molecular dynamics simulations of compound 1 and QST101 showed that both compounds bind stably to both proteins, with QST101 having a stronger binding capacity than compound 1. The analysis of protein-compound interactions showed that QST101 has good properties and can be a potential inhibitor of Src and Bcl-2 receptors.