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 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. 1. Introduction Alzheimer’s disease is the most common form of neurodegenerative disorders [1] characterized by the formation of extracellular deposits composed of amyloid beta peptide (A ) [2] and masses of paired, helically wound protein filaments in the cytoplasm of neuronal cell bodies and neuritic processes called neurofibrillary tangles [3]. These NFTs are formed as a result of hyperphosphorylation of tau protein [4]. The tau proteins are phosphoproteins whose levels of phosphorylation are regulated by tau kinases and phosphatases [5]. Substantial evidence reveals the increased activity of glycogen synthase kinase 3 (GSK3 ) (also known as human tau protein kinase I) during AD. Similarly, P25/cyclin-dependent kinase 5 (Cdk5), dual-specific tyrosine [Y] regulated kinase 1A (Dyrk1A), and mitogen-activated protein kinases (MAPK) also possess higher activity in AD brain [6]. Thus, our work focuses on the chosen 10 kinases involved in hyperphosphorylation of tau and elevated responses in AD [7]. Kinase holds a large gene family and these domains are alike in sequence and structure. Developments of discriminating inhibitors are a key task in drug discovery and development, and appreciating the basis of kinase