| Structural highlights
6h13 is a 2 chain structure with sequence from Tetronarce californica. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Activity: | Acetylcholinesterase, with EC number 3.1.1.7 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[ACES_TETCF] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. May be involved in cell-cell interactions.
Publication Abstract from PubMed
Both cholinesterases (AChE and BChE) and kinases, such as GSK-3alpha/beta, are associated with the pathology of Alzheimer's disease. Two scaffolds, targeting AChE (tacrine) and GSK-3alpha/beta (valmerin) simultaneously, were assembled, using copper(I)-catalysed azide alkyne cycloaddition (CuAAC), to generate a new series of multifunctional ligands. A series of eight multi-target directed ligands (MTDLs) was synthesized and evaluated in vitro and in cell cultures. Molecular docking studies, together with the crystal structures of three MTDL/TcAChE complexes, with three tacrine-valmerin hybrids allowed designing an appropriate linker containing a 1,2,3-triazole moiety whose incorporation preserved, and even increased, the original inhibitory potencies of the two selected pharmacophores toward the two targets. Most of the new derivatives exhibited nanomolar affinity for both targets, and the most potent compound of the series displayed inhibitory potencies of 9.5nM for human acetylcholinesterase (hAChE) and 7nM for GSK-3alpha/beta. These novel dual MTDLs may serve as suitable leads for further development, since, in the micromolar range, they exhibited low cytotoxicity on a panel of representative human cell lines including the human neuroblastoma cell line SH-SY5Y. Moreover, these tacrine-valmerin hybrids displayed a good ability to penetrate the blood-brain barrier (BBB) without interacting with efflux pumps such as P-gp.
Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3.,Oukoloff K, Coquelle N, Bartolini M, Naldi M, Le Guevel R, Bach S, Josselin B, Ruchaud S, Catto M, Pisani L, Denora N, Iacobazzi RM, Silman I, Sussman JL, Buron F, Colletier JP, Jean L, Routier S, Renard PY Eur J Med Chem. 2019 Apr 15;168:58-77. doi: 10.1016/j.ejmech.2018.12.063. Epub, 2019 Feb 13. PMID:30798053[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Oukoloff K, Coquelle N, Bartolini M, Naldi M, Le Guevel R, Bach S, Josselin B, Ruchaud S, Catto M, Pisani L, Denora N, Iacobazzi RM, Silman I, Sussman JL, Buron F, Colletier JP, Jean L, Routier S, Renard PY. Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3. Eur J Med Chem. 2019 Apr 15;168:58-77. doi: 10.1016/j.ejmech.2018.12.063. Epub, 2019 Feb 13. PMID:30798053 doi:http://dx.doi.org/10.1016/j.ejmech.2018.12.063
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