[Design of acetylcholinesterase inhibitor for Alzheimer's disease therapy: from multi-binding site inhibitors to multi-target directed ligands].
Alzheimer's disease (AD) is a complex neurodegenerative disorder which seriously causes the dementia in elderly people and afflicts millions of people worldwide. Drug discovery for Alzheimer's disease therapy has been a hot research area and a big challenge, in which development of acetylcholinesterase (AChE) inhibitors design was the most active and some AChE inhibitors are commercially available for AD medication already. However, practical using of commercial AChE inhibitors showed their limited usefulness and related adverse effects. Thus, it is extremely urgent to find novel AChE inhibitors with higher potency and less adverse effects. Based on the accurate crystallographic studies about AChE, strategies for multi-binding site AChE inhibitors have been formed, followed by design of the multi-target directed ligands. In this review, the structures and binding modes of commercial AChE inhibitors were briefly discussed, together with the development of AChE inhibitor design for AD therapy: from multi-binding site inhibitors to multi-target directed ligands.
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, China.
Wen-Chao
WC
Yang
Qi
Q
Sun
Ning-Xi
NX
Yu
Xiao-Lei
XL
Zhu
Guang-Fu
GF
Yang
D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human