Virtual screening of novel mTOR inhibitors for the potential treatment of human colorectal cancer

The substituted quinoline compound MT-5 was identified as a novel mTOR inhibitor via a rationally virtual screening strategy. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 μM) and antiproliferative effect against HCT-116 cells (IC50: 4.61 μM). MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, SD rat plasma, and liver microsomes. Computational studies of the MT-5 binding to mTOR protein have also been performed, which would provide a theoretical reference for further structural modification. [Display omitted] •A rationally virtual screening strategy has been established for mTOR inhibitors.•MT-5 was obtained from ChemDiv database, and it showed potent kinase inhibitory activity (IC50: 8.90 μM) and antiproliferative effect on HCT-116 cells (IC50: 4.61 μM).•The potential antitumor mechanism of MT-5 has been investigated.•MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, SD rat plasma and liver microsomes.•Computational studies of MT-5 binding to mTOR protein have also been performed. The abnormal activation of the mTOR pathway is closely related to the occurrence and progression of cancer, especially colorectal cancer. In this study, a rational virtual screening strategy has been established and MT-5, a novel mTOR inhibitor with a quinoline scaffold, was obtained from the ChemDiv database. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 μM) and antiproliferative effects against various cancer cell lines, especially HCT-116 cells (IC50: 4.61 μM), and this was 2.2-fold more potent than that of the cisplatin control (IC50: 9.99 μM). Western blot, cell migration, cycle arrest, and apoptosis assays were performed with HCT-116 cells to investigate the potential anticancer mechanism of MT-5. Metabolic stability results in vitro indicated that MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, rat plasma, and liver microsomes. In addition, the key contribution of the residues around the binding pocket of MT-5 in binding to the mTOR protein was also investigated from a computational perspective.