Cancer Stem Cells as Potential Targets of Phytotoxic Alkaloids from the Toxic Plants-Phytotoxins Database

Targeting cancer stem cells (CSCs) in anticancer discovery is very difficult due to the resistance of CSCs to conventional drugs. Different CSC targets, such as the ABC cassette, surface markers, signal cascade, and tumour microenvironment, are involved in the interruption of cell signalling pathways that are critical for the survival and functioning of the CSC population. The study aimed to identify potential drug-like phytotoxic alkaloids with anticancer activity from the toxic plants-phytotoxins (TPPTs) database. A total of 1586 phytotoxins were filtered to obtain 653 alkaloids. Lipinski’s properties and the TPSA were predicted for drug likeness and toxicity based on various organ endpoints. Compounds that obeyed Lipinski’s rule of five, with moderate or no toxicity were selected. The 11 drug-like phytotoxic alkaloids obtained from the filtering were docked on an isomerase-perdeuterated E65Q-TIM protein (ID: 7AZA; resolution = 1.10 Å) co-crystallized with phosphoglycolohydroxamate. The best binding poses were ranked using their binding energies (E) and inhibition constants (Ki). An evaluation of the protein—ligand’s best conformational poses allowed us to identify three indole alkaloids (catharanthine, (-)-eburnamonine and apovincamine) with significant protein—ligand binding interactions for (-)-eburnamonine (E = −8.03 kcal/mol; Ki = 1.30 μM), catharanthine (E = −8.229 kcal/mol; Ki = 0.910 μM) and apovincamine (E = −8.40 kcal/mol; Ki = 0.701 μM). All the docked ligands could bind more efficiently to the target than phosphoglycolohydroxamate. The efficient inhibition of perdeuterated E65Q-TIM in CSCs using phytotoxic alkaloids provided more insights into understanding the mechanisms of the anticancer activity of phytotoxic alkaloids.