Use of classical and 3-D QSAR to examine the hydration state of juvenile hormone esterase inhibitors

Craig E. Wheelock, Yoshiaki Nakagawa, Miki Akamatsu, Bruce D. Hammock

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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 (q2=0.412, m=6); however all cross-validated values for the gem-diol form of the inhibitors were not statistically significant (q2<0.3). Inclusion of hydrophobicity descriptors in both CoMFA equations increased their significance; however the final ketone equation (q2=0.500, m=7) was still statistically improved over the gem-diol (q2=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.

Original languageEnglish (US)
Pages (from-to)5101-5116
Number of pages16
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number23
DOIs
StatePublished - Nov 17 2003

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Quantitative Structure-Activity Relationship
Gems
Ketones
Hydration
Esterases
Carboxylic Ester Hydrolases
Agrochemicals
Detoxification
Enzymes
Hydrophobicity
Hydrophobic and Hydrophilic Interactions
Metabolism
Insects
juvenile hormone esterase
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Use of classical and 3-D QSAR to examine the hydration state of juvenile hormone esterase inhibitors. / Wheelock, Craig E.; Nakagawa, Yoshiaki; Akamatsu, Miki; Hammock, Bruce D.

In: Bioorganic and Medicinal Chemistry, Vol. 11, No. 23, 17.11.2003, p. 5101-5116.

Research output: Contribution to journalArticle

Wheelock, Craig E. ; Nakagawa, Yoshiaki ; Akamatsu, Miki ; Hammock, Bruce D. / Use of classical and 3-D QSAR to examine the hydration state of juvenile hormone esterase inhibitors. In: Bioorganic and Medicinal Chemistry. 2003 ; Vol. 11, No. 23. pp. 5101-5116.
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