Structure-based optimization of azole antifungal agents by CoMFA, CoMSIA, and molecular docking.
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.
Sheng
Chunquan
C
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
Zhang
Wannian
W
Ji
Haitao
H
Zhang
Min
M
Song
Yunlong
Y
Xu
Hui
H
Zhu
Jie
J
Miao
Zhenyuan
Z
Jiang
Qingfen
Q
Yao
Jianzhong
J
Zhou
Youjun
Y
Zhu
Jü
J
Lü
Jiaguo
J
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
D000935:Antifungal Agents; D001393:Azoles