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==Torpedo californica acetylcholinesterase in complex with a non-chiral donepezil-like inhibitor 17== | |||
<StructureSection load='5nap' size='340' side='right' caption='[[5nap]], [[Resolution|resolution]] 2.17Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5nap]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Tetronarce_californica Tetronarce californica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NAP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NAP FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=DZ7:(2~{E})-5,6-dimethoxy-2-[[1-(phenylmethyl)piperidin-4-yl]methylidene]-3~{H}-inden-1-one'>DZ7</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acetylcholinesterase Acetylcholinesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.7 3.1.1.7] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5nap FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nap OCA], [http://pdbe.org/5nap PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nap RCSB], [http://www.ebi.ac.uk/pdbsum/5nap PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nap ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/ACES_TETCF 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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Acetylcholinesterase inhibitors were introduced for the symptomatic treatment of Alzheimer's disease (AD). Among the currently approved inhibitors, donepezil (DNP) is one of the most preferred choices in AD therapy. The X-ray crystal structures of Torpedo californica AChE in complex with two novel rigid DNP-like analogs, compounds 1 and 2, have been determined. Kinetic studies indicated that compounds 1 and 2 show a mixed-type inhibition against TcAChE, with Ki values of 11.12 +/- 2.88 and 29.86 +/- 1.12 nM, respectively. The DNP rigidification results in a likely entropy-enthalpy compensation with solvation effects contributing primarily to AChE binding affinity. Molecular docking evidenced the molecular basis for the binding of compounds 1 and 2 to the active site of beta-secretase-1. Overall, these simplified DNP derivatives may represent new structural templates for the design of lead compounds for a more effective therapeutic strategy against AD by foreseeing a dual AChE and BACE-1 inhibitory activity. | |||
Kinetic and structural studies on the interactions of Torpedo californica acetylcholinesterase with two donepezil-like rigid analogues.,Caliandro R, Pesaresi A, Cariati L, Procopio A, Oliverio M, Lamba D J Enzyme Inhib Med Chem. 2018 Dec;33(1):794-803. doi:, 10.1080/14756366.2018.1458030. PMID:29651884<ref>PMID:29651884</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5nap" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Acetylcholinesterase]] | |||
[[Category: Tetronarce californica]] | |||
[[Category: Caliandro, R]] | [[Category: Caliandro, R]] | ||
[[Category: Lamba, D]] | [[Category: Lamba, D]] | ||
[[Category: Pesaresi, A]] | [[Category: Pesaresi, A]] | ||
[[Category: Alzheimer's disease]] | |||
[[Category: Donepezil analogue]] | |||
[[Category: Green chemistry]] | |||
[[Category: Hydrolase]] | |||
[[Category: Inhibitor]] | |||
Revision as of 10:56, 2 May 2018
Torpedo californica acetylcholinesterase in complex with a non-chiral donepezil-like inhibitor 17Torpedo californica acetylcholinesterase in complex with a non-chiral donepezil-like inhibitor 17
Structural highlights
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 PubMedAcetylcholinesterase inhibitors were introduced for the symptomatic treatment of Alzheimer's disease (AD). Among the currently approved inhibitors, donepezil (DNP) is one of the most preferred choices in AD therapy. The X-ray crystal structures of Torpedo californica AChE in complex with two novel rigid DNP-like analogs, compounds 1 and 2, have been determined. Kinetic studies indicated that compounds 1 and 2 show a mixed-type inhibition against TcAChE, with Ki values of 11.12 +/- 2.88 and 29.86 +/- 1.12 nM, respectively. The DNP rigidification results in a likely entropy-enthalpy compensation with solvation effects contributing primarily to AChE binding affinity. Molecular docking evidenced the molecular basis for the binding of compounds 1 and 2 to the active site of beta-secretase-1. Overall, these simplified DNP derivatives may represent new structural templates for the design of lead compounds for a more effective therapeutic strategy against AD by foreseeing a dual AChE and BACE-1 inhibitory activity. Kinetic and structural studies on the interactions of Torpedo californica acetylcholinesterase with two donepezil-like rigid analogues.,Caliandro R, Pesaresi A, Cariati L, Procopio A, Oliverio M, Lamba D J Enzyme Inhib Med Chem. 2018 Dec;33(1):794-803. doi:, 10.1080/14756366.2018.1458030. PMID:29651884[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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