In silico approximation of the interactions of acetogenins isolated from the root of Annona purpurea with the mitochondrial complex I.

Acetogenins are polyketides found almost exclusively in plants of the Annonaceae family and exhibit diverse biological activities, including antineoplastic, antiparasitic, cytotoxic, immunosuppressive, neurotoxic, and pesticidal effects. Five highly effective acetogenins (annopurpuricins A-E) showing anticancer properties in the picomolar range, were previously isolated from the roots of Annona purpurea (Hernández-Fuentes et al., 2019). To elucidate the mechanism underlying their potent cytotoxicity, we investigated the binding of annopurpuricins A-E to the ubiquinone-binding site of mitochondrial complex I using AutoDock Vina. Complex stability was assessed by molecular dynamics (MD) simulations. We identified the protein residues involved in binding and characterized the binding poses of the acetogenins. Annopurpuricins A-D adopted elongated conformations that spanned nearly the entire ubiquinone channel, whereas annopurpuricin E adopted a V-shaped conformation. Interactions were predominantly hydrophobic with a limited number of hydrogen bonds. These results support a model in which annopurpuricins inhibit complex I by occupying the ubiquinone channel, thus accounting for their exceptional cytotoxic potency.