Garcinol prevents hyperhomocysteinemia and enhances bioavailability of L-DOPA by inhibiting catechol-O-methyltransferase: an in silico approach

Abstract

Inhibition of catechol-O-methyltransferase (COMT), with drugs like tolcapone and entacapone, has been in practice to reduce L-DOPA-induced hyperhomocysteinemia in Parkinson’s disease (PD) patients. During L-DOPA methylation, S-adenosylhomocysteine is produced which is further processed to synthesize homocysteine (Hcy). Hcy has been reported to cause oxidative stress, excitotoxicity, DNA damage and neurodegeneration and is surmised to exaggerate motor complications in PD patients undergoing L-DOPA therapy. Moreover, COMT catalyzes the conversion of L-DOPA into 3-O-methyldopa (3-OMD) and dopamine (DA) into 3-methoxytyramine (3-MT). 3-OMD inhibits penetration of L-DOPA in brain as well as striatal uptake of the drug, while 3-MT is a neuromodulator which during further metabolism produces reactive oxygen species. Thus, COMT inhibition enhances the levels of L-DOPA and DA, which may be exploited to reduce the effective dose of L-DOPA in maintaining the levels of DA in PD patients, and thereby in treating the motor disorders by enhancing the bioavailability of the drug. Since presently used COMT inhibitors elicit several side effects, development of novel drugs is highly sought. Garcinol, a phyto-constituent, is a potent antioxidant and anti-inflammatory molecule effective against several disorders. However, its role in PD is unknown. Here, the COMT inhibitory potential of garcinol has been investigated using computational tools. The 3D structure of COMT, garcinol and tolcapone was downloaded from respective databases, and molecular docking was performed to obtain docking scores and interactions which revealed that garcinol binds to the active site of COMT similar to tolcapone. While tolcapone forms three hydrogen bonds and seven weak interactions with a docking score of −25.3575, garcinol forms four hydrogen bonds and nine weak interactions and has a docking score of −17.0983. Thus, the present study demonstrated garcinol to potentially interact with the active site of COMT and therefore inhibit the enzyme. Since COMT inhibition reduces Hcy levels, in addition to 3-OMD and 3-MT, as well as increases the bioavailability of DA and L-DOPA, the present study is of immense importance in the treatment of PD. Moreover, since garcinol is an established antioxidant and anti-inflammatory molecule, it may confer further neuroprotection and may emerge as a therapeutic anti-Parkinsonian drug in the future.