Computer-aided Discovery of Bioactive Natural Product Isoliquiritigenin as an Acetylcholinesterase Inhibitor

Abstract

Bioactive natural products have been extensively investigated for the discovery of alternative Alzheimer’s disease (AD) treatments. Recently, our structure-based virtual screening (SBVS) campaigns on natural products served in the LOTUS database exhibited the potency of isoliquiritigenin as an acetylcholinesterase (AChE) inhibitor, which propelled us to investigate it further. This study aimed to evaluate the acetylcholinesterase (AChE) inhibitory activity of isoliquiritigenin compared to commonly known inhibitors, i.e., donepezil, through in vitro and in silico studies. The AChE inhibitory activity of isoliquiritigenin and donepezil was evaluated using the improved Ellman method, and the molecular mechanism for inhibiting AChE was identified using molecular docking and dynamics simulations. Our findings verified the AChE inhibitory activity of isoliquiritigenin, possessing an IC50 value of 126.22 µM compared to donepezil, with an IC50 value of 36.98 µM. In silico studies revealed that five best-docked poses from 100 redocking and molecular docking simulations established interactions in the AChE active site in 5 ns after 5-ns equilibration run. Further dynamics interactions were explored to 50 ns, showing interactions of isoliquiritigenin and donepezil, which were still in the AChE active site. These simulations also revealed the pivotality of the aromatic ring and hydroxyl moiety of isoliquiritigenin reinforcing the receptor-ligand stabilization. Hence, our studies exhibited the potency of isoliquiritigenin acting as an AChE inhibitor and might be explored in isoliquiritigenin-containing bioactive natural products as AD alternative treatments.