Abstract

14 alpha-Demethylase (CYP51) inhibitors have been widely used in the treatment of fungal infections. In this study, a series of imidazole derivatives with CYP51 inhibitory activity were subjected to a molecular docking study followed by quantitative structure-activity relationship (QSAR) analyses in search of the ideal physicochemical characteristics of potential CYP51 inhibitors. Desired imidazoles were built using the HyperChem program, and conformational studies were performed through a semiempirical method followed by the PM3 method. Docking study was performed using the AutoDock program on all of the compounds. Different QSAR descriptors were calculated using DRAGON, AutoDock, and HyperChem. Multilinear regression was used as a chemometric tool for QSAR modeling. The docking study indicated that all of compounds 1-43 interact with the 14 alpha-demethylase, and azole-heme coordination and pi - pi and pi-cation interactions are involved in drug-receptor interaction. In the pi - pi and pi-cation interactions, the aryl moieties interact with Phe 255 and Arg 96, and the role of the phenoxy group is more important than that of the phenyl group. The developed QSAR model indicated the importance of atomic van der Waals volumes and atomic Sanderson electronegativities. The sums of the R6u, RDF030v, Mor25v, GATs5e, and R5e+ were identified as the most significant descriptors. The developed QSAR model was statistically significant according to the validation parameters.