Mechanisms of Phorbol Ester Toxicity, Determined by Molecular Modelling

Phorbol esters are toxic phytochemicals, whose main biological target is protein kinase C. They bind irreversibly to the protein, causing cell damage. Using computer modelling, we have determined, for the first time, features and mechanisms that lead to the toxicity of phorbol esters.

Protein kinase C – delta (PKC-δ) was used as a target protein in computational docking studies with phorbol esters that differ in molecular structure. Binding conformations and stability of ester linkages were analyzed to evaluate their relationship with experimental observations. Results show that an active phorbol ester must exhibit two features: interaction with specific amino acid residues at the binding site and covering the area with a hydrophobic surface. Toxicity of an active phorbol ester is inversely proportional to the intrinsic reactivity of the ester linkage. Phorbol esters bearing free acid chains can directly activate PKC-δ but jatropha phorbol esters are restricted by their acid-moiety ring formations, suggesting similar mechanism of interaction with other phorbol-ester protein targets.