Exploring the Therapeutic Potential of Ar-tur in Alzheimer Disease: A Cheminformatics, Pharmacokinetics, and System Pharmacology Approach.

Abstract

Acquisition and consolidation of recognition memory involves dopaminergic activity, which is determined to be dysregulated in Alzheimer disease (AD). Aromatic turmerone (Ar-tur), one of the major bioactive components of Curcuma longa, has been identified to protect dopaminergic neurons from various pathological insults. We have computationally investigated the drug-like nature and the therapeutic potential of Ar-tur in treating AD and have compared its targets with FDA-approved AD drugs. Cheminformatics, pharmacokinetics, toxicity, and system pharmacology studies were performed in predicting the drug-like properties, protein targets, toxicity profiles, target's functional association, and enrichment analysis of Ar-tur. Notably, Ar-tur had targeted 94 proteins, and 29 proteins of these proteins were among the top 15 targets of the 20 FDA-approved drugs. These targets were identified to be dysregulated in the hippocampus and entorhinal cortex in the AD brain, signifying that targets of Ar-tur play roles in disease modification and regulation. Based on gene ontology analysis, KEGG, Reactome, and WikiPathways, we identified that Ar-tur regulates dopamine neurotransmitter receptor activity and dopamine binding activity. Dopamine receptors (DRs), DR2 and DR4, were among its top 15 targets of Ar-tur. Molecular docking of DRs with dopamine, cariprazine, brexpiprazole, RO-10-5824, CP226269, and donepezil connotes that Ar-tur behaves like an agonist of DR2 and DR4 by binding to the active site residues like the dopamine and DR agonists. This is the first report stating the impressive drug-like properties of Ar-tur and holds the potential to rescue the vulnerable dopaminergic system by regulating DRs.