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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
23
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pubmed:dateCreated |
2006-12-12
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pubmed:abstractText |
The acetylcholinesterase (AChE) inhibitory activity of a series of 13-amido derivatives of huprine Y, designed to enlarge the occupancy of the catalytic binding site by mimicking the piridone moiety present in (-)-huperzine A, has been assessed. Although both 13-formamido and 13-methanesulfonamido derivatives are more potent human AChE inhibitors than tacrine and (-)-huperzine A, none of them equals the potency of huprine Y. Molecular modeling studies show that the two derivatives effectively trigger the Gly117-Gly118 conformational flip induced upon binding of (-)-huperzine A, leading to a similar pattern of interactions as that formed by the pyridone amido group of (-)-huperzine A. The detrimental effect on the binding affinity relative to the 13-unsubstituted huprine could be ascribed to a sizable deformation cost associated with the ligand-induced peptide flip. This finding can be interpreted as a mechanism selected by evolution to ensure the preorganization of the functionally relevant oxyanion hole in the binding site of AChE, where residues Gly117 and Gly118 play a relevant role in mediating substrate recognition.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Acetylcholinesterase,
http://linkedlifedata.com/resource/pubmed/chemical/Alkaloids,
http://linkedlifedata.com/resource/pubmed/chemical/Aminoquinolines,
http://linkedlifedata.com/resource/pubmed/chemical/Anions,
http://linkedlifedata.com/resource/pubmed/chemical/Cholinesterase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Formamides,
http://linkedlifedata.com/resource/pubmed/chemical/Glycine,
http://linkedlifedata.com/resource/pubmed/chemical/Heterocyclic Compounds with 4 or...,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Sesquiterpenes,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfonamides,
http://linkedlifedata.com/resource/pubmed/chemical/Tacrine,
http://linkedlifedata.com/resource/pubmed/chemical/huperzine A,
http://linkedlifedata.com/resource/pubmed/chemical/huprine X,
http://linkedlifedata.com/resource/pubmed/chemical/huprine Y
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
16
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pubmed:volume |
49
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
6833-40
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:17154513-Acetylcholinesterase,
pubmed-meshheading:17154513-Alkaloids,
pubmed-meshheading:17154513-Aminoquinolines,
pubmed-meshheading:17154513-Animals,
pubmed-meshheading:17154513-Anions,
pubmed-meshheading:17154513-Catalytic Domain,
pubmed-meshheading:17154513-Cattle,
pubmed-meshheading:17154513-Cholinesterase Inhibitors,
pubmed-meshheading:17154513-Erythrocytes,
pubmed-meshheading:17154513-Formamides,
pubmed-meshheading:17154513-Glycine,
pubmed-meshheading:17154513-Heterocyclic Compounds with 4 or More Rings,
pubmed-meshheading:17154513-Humans,
pubmed-meshheading:17154513-Ligands,
pubmed-meshheading:17154513-Models, Molecular,
pubmed-meshheading:17154513-Protein Binding,
pubmed-meshheading:17154513-Protein Conformation,
pubmed-meshheading:17154513-Sesquiterpenes,
pubmed-meshheading:17154513-Stereoisomerism,
pubmed-meshheading:17154513-Structure-Activity Relationship,
pubmed-meshheading:17154513-Sulfonamides,
pubmed-meshheading:17154513-Tacrine
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pubmed:year |
2006
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pubmed:articleTitle |
Binding of 13-amidohuprines to acetylcholinesterase: exploring the ligand-induced conformational change of the gly117-gly118 peptide bond in the oxyanion hole.
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pubmed:affiliation |
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal 643, E-08028, Barcelona, Spain.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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