Inhibition of catechol-<i>O</i>-methyltransferase by natural pentacyclic triterpenes: structure–activity relationships and kinetic mechanism

Inhibitors of COMT are clinically used for the treatment Parkinson’s disease. Here, we report first natural pentacyclic triterpenoid-type inhibitors and their structure-activity relationships inhibition mechanism. The most potent compounds were found to be oleanic acid, betulinic acid celastrol with IC50 values 3.89–5.07 μM, that acted as mixed (uncompetitive plus non-competitive) COMT, representing a new skeleton inhibitor. Molecular docking suggested they can specifically recognise bind unique hydrophobic residues surrounding catechol pocket. Furthermore, proved less disruptive mitochondrial membrane potential (MMP) compared tolcapone, thus reducing risk liver toxicity. These findings could produce an ideal lead compound guide synthetic efforts in generating related derivatives further preclinical testing.