title: Structure-based optimization of azole antifungal agents by CoMFA, CoMSIA, and molecular docking.
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.
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Song
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.forename: Qingfen
authors.initials: Q
authors.lastname: Jiang
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Youjun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jü
authors.initials: J
authors.lastname: Zhu
authors.forename: Jiaguo
authors.initials: J
authors.lastname: Lü
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D016208:Databases, Factual; D005658:Fungi / Q000187:drug effects; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D001393:Azoles