Comparative molecular field analysis of fungal squalene epoxidase inhibitors

Comparative molecular field analysis (CoMFA) of fungal squalene epoxidase i nhibitors exhibiting antifungal activity reported in terms of minimum inhib itory concentration (MIC) was performed. Ninety-two molecules belonging to different chemical classes, namely terbinafine analogues, benzylamines, hom opropargylamines, and carbon analogues were divided into training set and t est set. The initial conformations of the inhibitors obtained from molecula r 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 i n models with good internal predictivity. Initial analysis of 92 molecules (analysis A) resulted in models with low predictive r(2) values for activit y against three organisms. This data set was modified by exclusion of 13 mo lecules, and analysis was performed again. This analysis of 79 molecules (a nalysis B) resulted in improvement in predictivity of the CoMFA models and cross-validated r(2) values of 0.583, 0.509, and 0.502 for Candida albicans , Aspergillus fumigatus, and Trichophyton mentagrophytes, respectively. The se models were used to predict the activities of the molecules belonging to the test set. The models from analysis B show better correlative and predi ctive properties than analysis A. Comparison of CoMFA contour maps for acti vity against three different fungi revealed differentiating structural requ irements.