Preferential selectivity of inhibitors with human tau protein kinase Gsk3 β elucidates their potential roles for off-target Alzheimer's therapy

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid beta peptides (A β) and neurofibrillary tangles (NFTs). The abnormal phosphorylation of tau leads to the formation of NFTs produced by the action of tau kinases, resulting in the loss of neurons and synapse, leading to dementia. Hence, tau kinases have become potential drug target candidates for small molecule inhibitors. With an aim to explore the identification of a common inhibitor, this investigation was undertaken towards analyzing all 10 tau kinases which are implicated in phosphorylation of AD. A set of 7 inhibitors with varied scaffolds were collected from the Protein Data Bank (PDB). The analysis, involving multiple sequence alignment, 3D structural alignment, catalytic active site overlap, and docking studies, has enabled elucidation of the pharmacophoric patterns for the class of 7 inhibitors. Our results divulge that tau protein kinases share a specific set of conserved structural elements for the binding of inhibitors and ATP, respectively. The scaffold of 3-aminopyrrolidine (inhibitor 6) exhibits high preferential affinity with GSK3 β. Surprisingly, the PDB does not contain the structural details of GSK3 β with this specific inhibitor. Thus, our investigations provide vital clues towards design of novel off-target drugs for Alzheimer's. © 2013 Jagadeesh Kumar Dasappa and H. G. Nagendra.