Linked Life Data

14604674

Source:http://linkedlifedata.com/resource/pubmed/id/14604674

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
23
pubmed:dateCreated
2003-11-7
pubmed:abstractText
Carboxylesterases are important enzymes in the metabolism of numerous pharmaceuticals and agrochemicals. They are of importance in many detoxification pathways, but their endogenous role remains unclear. The most potent esterase inhibitors found to date are trifluoromethylketone (TFK) containing compounds, which have been shown to inhibit both mammalian and insect esterases at the low nM level. The detailed mechanism by which these compounds inhibit the enzyme is still unclear. They are highly hydrated in aqueous solutions, but their mechanism of inhibition suggests that inhibition occurs through the ketone, not the hydrated gem-diol. Some studies have stated that the ketone is the inhibitor, while others have reported the gem-diol as the active form. Using juvenile hormone esterase (JHE) as a model system, we examined this question using both classical QSAR and 3-D QSAR with comparative molecular field analysis (CoMFA). Classical QSAR analyses demonstrated the high dependence of inhibitor potency upon log P as well as the limitations of sterically unfavorable substituents. The ketone form of the inhibitor consistently provided improved correlations over the gem-diol, with the final equations describing 72 and 69% of inhibitor activity, respectively, for 97 compounds. Initial CoMFA analyses for the ketone provided a significant equation for 108 compounds (q(2)=0.412, m=6); however all cross-validated values for the gem-diol form of the inhibitors were not statistically significant (q(2)<0.3). Inclusion of hydrophobicity descriptors in both CoMFA equations increased their significance; however the final ketone equation (q(2)=0.500, m=7) was still statistically improved over the gem-diol (q(2)=0.506, m=8). These results support those obtained for the classical QSAR analysis and further illustrate the importance of log P in the inhibition mechanism of these inhibitors. The CoMFA models also identified novel target areas for the synthesis of new JHE inhibitors. These results suggest that the ketone is the active form of TFK-containing inhibitors.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0968-0896
pubmed:author
pubmed:issnType
Print
pubmed:day
17
pubmed:volume
11
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5101-16
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Use of classical and 3-D QSAR to examine the hydration state of juvenile hormone esterase inhibitors.
pubmed:affiliation
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't