Comparative molecular field analysis of fungal squalene epoxidase inhibitors

Vijay M. Gokhale, Vithal M. Kulkarni

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Comparative molecular field analysis (CoMFA) of fungal squalene epoxidase inhibitors exhibiting antifungal activity reported in terms of minimum inhibitory concentration (MIC) was performed. Ninety-two molecules belonging to different chemical classes, namely terbinafine analogues, benzylamines, homopropargylamines, and carbon analogues were divided into training set and test set. The initial conformations of the inhibitors obtained from molecular dynamics simulations for 50 ps in aqueous solution were used in the study. Out of three charges used in the study, Gasteiger-Huckel charges result in models with good internal predictivity. Initial analysis of 92 molecules (analysis A) resulted in models with low predictive r2 values for activity against three organisms. This data set was modified by exclusion of 13 molecules, and analysis was performed again. This analysis of 79 molecules (analysis B) resulted in improvement in predictivity of the CoMFA models and cross- validated r2 values of 0.583, 0.509, and 0.502 for Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes, respectively. These models were used to predict the activities of the molecules belonging to the test set. The models from analysis B show better correlative and predictive properties than analysis A. Comparison of CoMFA contour maps for activity against three different fungi revealed differentiating structural requirements.

Original languageEnglish (US)
Pages (from-to)5348-5358
Number of pages11
JournalJournal of Medicinal Chemistry
Volume42
Issue number26
DOIs
StatePublished - Dec 30 1999

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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