7D9P

Crystal Structure of Recombinant Human Acetylcholinesterase in Complex with Compound 12

Summary for 7D9P

• Entry DOI: 10.2210/pdb7d9p/pdb
• Descriptor: Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, (2S)-2-[[4-fluoranyl-1-[(2-fluorophenyl)methyl]piperidin-4-yl]methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one (3 entities in total)
• Functional Keywords: ache inhibitor, complex structure, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 123623.05

Authors

Liu, Q.F.,Yin, W.C. (deposition date: 2020-10-14, release date: 2021-08-25, Last modification date: 2024-11-06)

Primary citation

Zhou, Y.,Fu, Y.,Yin, W.,Li, J.,Wang, W.,Bai, F.,Xu, S.,Gong, Q.,Peng, T.,Hong, Y.,Zhang, D.,Zhang, D.,Liu, Q.,Xu, Y.,Xu, H.E.,Zhang, H.,Jiang, H.,Liu, H.
Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate.
J.Med.Chem., 64:1844-1855, 2021

PubMed Abstract: The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between and AChE. Besides, the data from the phase I trials demonstrated that had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.

PubMed: 33570950
DOI: 10.1021/acs.jmedchem.0c01863

Experimental method

X-RAY DIFFRACTION (2.85 Å)