Structure-Based Optimization of Azole Antifungal Agents by CoMFA, CoMSIA, and Molecular Docking
- 22 March 2006
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 49 (8), 2512-2525
- https://doi.org/10.1021/jm051211n
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 14α-demethylase was further explored using the flexible docking method. Various hydrophobic, van der Waals, π−π 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.Keywords
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