Development of Pharmacophore Alignment Models as Input for Comparative Molecular Field Analysis of a Diverse Set of Azole Antifungal Agents

Molecular modeling studies were performed on a diverse set of 24 cytochrome P-450 14 α DM inhibiting azole antifungals that demonstrate different degrees of biological activity. The studied compounds, which have been reported to be active in vitro against Candida albicans, were divided into a training set of 20 compounds and a test set of 4 compounds. In an effort to develop a ligand-binding model for the cytochrome P-450 14 α DM receptor, a pharmacophore mapping program (Apex-3D) was used to search structural features that are common to ligands that exhibit moderate to high antifungal activity. Apex-3D then was utilized to propose a common biophoric region that included one low-energy conformation of each compound in the training set. These aligned structures suggested a three-point pharmacophore map (two atom-centered descriptors and one aromatic ring centroid) for the azole antifungals. The resulting alignment was used in a comparative molecular field analysis (CoMFA) study in an attempt to correlate the steric and electrostatic fields of the compounds with the respective biological activity. The predictive ability of each resultant CoMFA model was evaluated using a test set consisting of four compounds. The best 3D quantitative structure−activity relationship model yielded cross-validated, conventional, and predictive r 2 values equal to 0.536, 0.998, and 0.778, respectively. A predictive model was obtained from the CoMFA analysis, which shall be useful for the development of new azole analogues as potential antifungals.