AchE-OGT dual inhibitors: Potential Partners in Handling Alzheimer’s Disease

Abstract

The emerging role of O-GlcNAc Transferase (OGT) and tau protein in Alzheimers disease (AD) holds promises for the treatment of this life-threatening neurodegenerative disorder. In view of the availability of 3D structure of OGT, we attempted to develop structure-based pharmacophore model to elucidate specific structural requirements for binding of inhibitors to the active site of OGT. During the course of study we discovered that donepezil, an old and trusted Acetylcholinesterase (AchE) inhibitor also possess the pharmacophoric sites important for interaction with OGT active site. To further explore the specific interactions of donepezil with OGT, we performed molecular docking studies using CDocker. The results of molecular docking and structure-based pharmacophore mapping revealed that donepezil has the required structural features to interact with various OGT active site amino acids like Lys842, His920, Leu653, Gly654, Asn838, and Thr921 in addition to its AchE interaction abilities. Our findings could be an important breakthrough in the design of OGT specific and/or AchE OGT dual inhibitors.