Document Report Card

ID: ALA1146065

Journal: J Med Chem

Title: Structure-based optimization of azole antifungal agents by CoMFA, CoMSIA, and molecular docking.

Authors: Sheng C, Zhang W, Ji H, Zhang M, Song Y, Xu H, Zhu J, Miao Z, Jiang Q, Yao J, Zhou Y, Zhu J, Lü J.

Abstract: In a continuing effort to develop highly potent azole antifungal agents, the three-dimensional quantitative structure-activity relationship methods, CoMFA and CoMSIA, were applied using a set of novel azole antifungal compounds. The binding mode of the compounds at the active site of lanosterol 14alpha-demethylase was further explored using the flexible docking method. Various hydrophobic, van der Waals, pi-pi stacking, and hydrogen bonding interactions were observed between the azoles and the enzyme. Based on results from the molecular modeling, a receptor-based pharmacophore model was established to guide the rational optimization of the azole antifungal agents. Thus, a total of 57 novel azoles were designed and synthesized by a three-step optimization process. In vitro antifungal assay revealed that the antifungal activities of these novel azoles were greatly improved, which confirmed the reliability of the model from molecular modeling.

CiteXplore: 16610794

DOI: 10.1021/jm051211n