Isocorilagin, a cholinesterase inhibitor from Phyllanthus niruri

Abstract

Drugs that have dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) produce better clinical efficacy against Alzheimer's disease (AD) than those that selectively inhibit one enzyme. A dual cholinesterase inhibitory-guided fractionation of Phyllanthus niruri leaves afforded isocorilagin, a bioactive tannin possessing good inhibitory activities against AChE (IC50: 0.49 μM) and BChE (IC50: 4.20 μM). Interestingly, isocorilagin was relatively 2- to 3-fold more potent than galanthamine, the clinically used inhibitor. The kinetic analyses suggested that isocorilagin was a non-competitive inhibitor for AChE and an uncompetitive inhibitor for BChE, with calculated Ki values of 1.49 μM and 2.86 μM, respectively. In silico molecular docking revealed that isocorilagin effectively blocked the substrate entry by forming hydrogen bonding with residues at the entrance of the AChE active site. With BChE, the compound completely docked inside and occupied the active site of the enzyme. This study demonstrated for the first time the potent cholinesterase inhibitory activities of isocorilagin, a promising lead that is worthy of further investigation.