Preferential Selectivity of Inhibitors with Human Tau Protein Kinase Gsk3 Elucidates Their Potential Roles for Off-Target Alzheimer’s Therapy
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid beta peptides (A) 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...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Hindawi Limited
2013-01-01
|
| Series: | International Journal of Alzheimer's Disease |
| Online Access: | http://dx.doi.org/10.1155/2013/809386 |
| Summary: | Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid beta
peptides (A) 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.
Surprisingly, the PDB does not contain the structural details of GSK3 with this specific inhibitor.
Thus, our investigations provide vital clues towards design of novel off-target drugs for Alzheimer’s. |
|---|---|
| ISSN: | 2090-8024 2090-0252 |