7d9p: Difference between revisions

Latest revision as of 13:31, 6 November 2024

Crystal Structure of Recombinant Human Acetylcholinesterase in Complex with Compound 12

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.85Å
Ligands:	FUC, H0R, NAG
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

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 12 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 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 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.

Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate.,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 HE, Zhang H, Jiang H, Liu H J Med Chem. 2021 Feb 25;64(4):1844-1855. doi: 10.1021/acs.jmedchem.0c01863. Epub , 2021 Feb 11. PMID:33570950^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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 HE, Zhang H, Jiang H, Liu H. Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate. J Med Chem. 2021 Feb 25;64(4):1844-1855. PMID:33570950 doi:10.1021/acs.jmedchem.0c01863

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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 HE, Zhang H, Jiang H, Liu H. Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate. J Med Chem. 2021 Feb 25;64(4):1844-1855. PMID:33570950 doi:10.1021/acs.jmedchem.0c01863

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='7d9p' size='340' side='right'caption='[[7d9p]], [[Resolution|resolution]] 2.85&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7d9p]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7D9P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D9P FirstGlance]. <br>
+<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7D9P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D9P FirstGlance]. <br>
 </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.85&#8491;</td></tr>
 <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=H0R:(2S)-2-[[4-fluoranyl-1-[(2-fluorophenyl)methyl]piperidin-4-yl]methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one'>H0R</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7d9p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d9p OCA], [https://pdbe.org/7d9p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d9p RCSB], [https://www.ebi.ac.uk/pdbsum/7d9p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d9p ProSAT]</span></td></tr>
 </table>
-== Function ==
-[https://www.uniprot.org/uniprot/ACES_HUMAN ACES_HUMAN] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.<ref>PMID:2714437</ref> <ref>PMID:1748670</ref> <ref>PMID:1517212</ref> <ref>PMID:11985878</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
 [[Category: Large Structures]]
 [[Category: Liu QF]]
 [[Category: Yin WC]]

7d9p: Difference between revisions

Latest revision as of 13:31, 6 November 2024

Crystal Structure of Recombinant Human Acetylcholinesterase in Complex with Compound 12

Structural highlights

Publication Abstract from PubMed

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