Acetylcholine-esterase (AchE) inhibitors are one of the most potent drug molecules against Alzheimer's disease (AD). But, patients treated with current AchE inhibitors often experience severe side effects. Quercetin is a plant flavonoid compound which can act as AchE inhibitor and it may be a better alternative to current AchE inhibitors in terms of effectiveness with no or fewer side effects.

Aims: The aim of the study was to compare quercetin with conventional AchE inhibitors to search for a better drug candidate.

Methods and materials: Physico-chemical properties of conventional drugs and quercetin were predicted using bioinformatics tools. Molecular docking of these compounds on the active site of AchE was performed using AutoDock and comparative analysis was performed. Later, modification on the basic structure of quercetin with different functional groups was done to perform QSAR analysis.

Result and discussion: Quercetin showed a similar drug likeness score to the conventional drugs. The binding strength for quercetin in the active site of the enzyme was -8.8 kcal/mol, which was considerably higher than binding scores for some of the drugs such as donepezil (binding score -7.9 kcal/mol). Fifteen hydrogen bonds were predicted between quercetin and the enzyme whereas conventional drugs had fewer or even no hydrogen bonds. It implies that quercetin can act as a better inhibitor than conventional drugs. To find out even better inhibitor, similar structures of quercetin were searched through SIMCOMP database and a methylation in the 4-OH position of the molecule showed better binding affinity than parent quercetin. Quantitative structure activity relationship study indicated that O-4 methylation was specifically responsible for better affinity.

Conclusion: This in silico study has conclusively predicted the superiority of the natural compound quercetin over the conventional drugs as AchE inhibitor and it sets the need for further in-vitro study of this compound in future.