Abstract
c-Jun N-terminal kinase (JNK) plays an important role in cell death caused by various stimuli. Because the isoform JNK3 is mainly expressed in the brain, it is believed to play a pivotal role in various neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), which still lack plausible therapeutics. To develop a novel and selective JNK3 inhibitor, we conducted a decadal review (2011 to 2021) of published articles on JNK inhibitors, particularly those focusing on a structural perspective and docking insights. We observed the structures of three isoforms of JNK, namely holo-proteins and co-crystal structures, with JNK3 inhibitors and summarized the significant structural aspects of selective JNK3 inhibitors as AD therapeutics.
Highlights
Protein kinases were discovered more than 65 years ago, but they have been therapeutic targets for less than 30 years [1,2]
The compound-induced movement of methionine residues in the JNK2 structure and the formation of a hydrophobic pocket are more common in JNK3 structures
Alzheimer’s disease (AD) is a disease with huge untherapeutic needs that requires new therapeutic molecular targets
Summary
Inhibitors as Therapeutics for Alzheimer’s Disease: Investigating Structure through Docking Studies. Because the isoform JNK3 is mainly expressed in the brain, it is believed to play a pivotal role in various neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), which still lack plausible therapeutics. To develop a novel and selective JNK3 inhibitor, we conducted a decadal review (2011 to 2021) of published articles on JNK inhibitors, those focusing on a structural perspective and docking insights. We observed the structures of three isoforms of JNK, namely holo-proteins and co-crystal structures, with JNK3 inhibitors and summarized the significant structural aspects of selective JNK3 inhibitors as AD therapeutics. Perspective on the Development of c-Jun N-terminal Kinase Inhibitors as Keywords: Alzheimer’s disease; c-Jun N-terminal kinase; small-molecule protein kinase inhibitor; JNK3; selectivity.
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