Deciphering inhibitory activity of flavonoids against tau protein kinases: a coupled molecular docking and quantum chemical study

Abstract

Today, Alzheimer’s disease (AD) is one of the most important neurodegenerative disorders that affected millions of people around the world. Hundreds of academic investigations highlighted the potential roles of natural metabolites in the cornerstone of AD prevention. Nevertheless, alkaloids are only metabolites that successfully showed promising clinical therapeutic effects on the prevention of AD. In this regard, other classes of plant metabolites such as flavonoids are also considered to be promising substances in the improvement of AD complications. The lack of data on molecular mode of action of flavonoids inside brain tissues, and their potential to transport across the blood-brain barrier, a physical hindrance between bloodstream and brain tissues, limited the large-scale application of these compounds for AD therapy programs. Herein, a coupled docking and quantum study was applied to determine the binding mode of flavonoids and three protein kinases involved in the pathogenesis of AD. The results suggested that all docked metabolites showed considerable binding affinity to interact with target receptors, but some compounds possessed higher binding energy values. Because docking simulation cannot entirely reveal the potential roles of ligand substructures in the interaction with target residues, quantum chemical analyses (QCAs) were performed to cover this drawback. Accordingly, QCAs determined that distribution of molecular orbitals have a pivotal function in the determination of the type of reaction between ligands and receptors; therefore, using such quantum chemical descriptors may correct the results of virtual docking outcomes to highlight promising backbones for further developments.