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

Abstract

The emerging role of O-GlcNAc Transferase (OGT) and tau protein in Alzheimer's 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.

Pharmacophore-driven identification of N-methyl-D-receptor antagonists as potent neuroprotective agents validated using in vivo studies

“…The lead compounds with good fit values, estimated activity, drug-likeness, and docking score are checked for novelty by employing pairwise Tanimoto similarity indices using “Find Similar Molecules by Fingerprint” in Discovery Studio (DS). In this study, all the lead compounds show low Tanimoto similarity indices to all the structures of known NMDA receptors antagonists validating their uniqueness [ 12 ]. The third phase entails molecular docking studies that succeeded by evaluating the retrieved potent lead compounds for neuroprotective activity.…”

Pharmacophore-driven Identification of N-Methyl-D-Receptor Antagonists as Potent Neuroprotective Agents Validated UsingIn-VivoStudies

“…The lead compounds obtained from ligand based database search were subjected to docking studies to check the type of molecular interactions 25 . Molecular Docking studies were carried out using the programme LibDocker which is a molecular dynamics simulated annealing based algorithm and available as an extension of DS V.2.0 26 . The crystal structure of NMDARs obtained from PDB was used for docking.…”

“…The protein part was labeled as a receptor molecule while the ligand was utilized to delineate the binding site of approximately 9 Angstroms on the receptor molecule. The chemical structure of the test compound was sketched and subjected to energy minimization in order to get the highly stable structure for molecular docking studies 26, 27, 28 . Based on present coordinates, marketed drug and test compounds were employed to molecular docking studies and all the parameters were set to their default values.…”