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

Abstract

Inhibitors of COMT are clinically used for the treatment of Parkinson's disease. Here, we report the first natural pentacyclic triterpenoid-type COMT inhibitors and their structure-activity relationships and inhibition mechanism. The most potent compounds were found to be oleanic acid, betulinic acid and celastrol with IC 50 values of 3.89-5.07 lM, that acted as mixed (uncompetitive plus non-competitive) inhibitors of COMT, representing a new skeleton of COMT inhibitor. Molecular docking suggested that they can specifically recognise and bind with the unique hydrophobic residues surrounding the catechol pocket. Furthermore, oleanic acid and betulinic acid proved to be less disruptive of mitochondrial membrane potential (MMP) compared to tolcapone, thus reducing the risk of liver toxicity. These findings could be used to produce an ideal lead compound and to guide synthetic efforts in generating related derivatives for further preclinical testing.

Effects of quercetin in preclinical models of Parkinson's disease: A systematic review

“…Protein kinase D1 (PKD1‐Akt) survival signalling pathways are also triggered, also optimizing mitochondrial energy production 29,96 . QUE also decreases mitochondrial ROS production 91 while increases the levels of PTEN Induced Kinase 1 (PINK1) and parkin mitophagy markers, and levels of tyrosine hydroxylase and α‐synuclein aggregates are also compensated for by Pink1 or parkin siRNA 97 . QUE inhibits of α‐synuclein accumulation, mitochondrial destruction and cell death in the mouse model of PD 97 …”

“…97 QUE inhibits of α-synuclein accumulation, mitochondrial destruction and cell death in the mouse model of PD. 97…”

Therapeutic considerations of bioactive compounds in Alzheimer's disease and Parkinson's disease: Dissecting the molecular pathways

“…Similarly, along with ameliorating oxidative stress, mitochondrial dysfunction and neuroinflammation, celastrol is found to induce autophagy, reduce α‐synuclein levels and dopaminergic neuron death and improve motor functions in PD cell and mouse models (Deng et al, 2013; Lin, Lin, et al, 2020; Zhang, Zhao, et al, 2021). Further, an in silico and in vitro study reported the COMT inhibitory potential of celastrol indicating its therapeutic efficiency as an anti‐PD drug (Wang, Wei, et al, 2021). Lycopene , abundantly found in tomatoes, papaya, guava and so on, is reported to exert neuroprotection in several disease models including AD, PD and HD (Paul et al, 2020).…”