Insight into the structural requirement of Cytochrome P450 lanosterol 14α-demethylase inhibitors based on 3D-QSAR and Molecular Docking

To investigate the structural requirements of Cytochrome P450 lanosterol 14α-demethylase (CYP51) inhibition for the series of triazole derivatives as antifungal agents, a three-dimensional quantitative structure activity relationship (3D-QSAR) using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were performed. Assessment of 24 compounds as training set served to set up model, while it was validated by assessment of a set of 9 test set compounds. Most potent molecule with least energy conformer obtained from the systematic search was used as a template structure for the alignment of the data set. The optimum partial least squares (PLS) for CoMFA and CoMSIA models illustrated good ‘leave-one-out’ crossvalidated coefficient (q2) of 0.611 and 0.792, the coefficient of determination (r 2) of 0.982 and 0.953 and good predicted power (r 2pred) of 0.871 and 0.752 respectively. Docking results showed that those compounds which have capability to interact with heme group could possess high inhibitory activity. The final models of QSAR along with information gathered from contour maps and docking study may be used for designing of novel analogs as potential antifungal agents.