期刊
FUTURE MEDICINAL CHEMISTRY
卷 12, 期 9, 页码 763-774出版社
FUTURE SCI LTD
DOI: 10.4155/fmc-2019-0289
关键词
antifungal activity; fusidic acid; homology modeling; molecular docking; molecular dynamics simulations
资金
- National Natural Science Foundation of China [81603024, 81773563]
- Key Research Project of Shandong Province [2019GSF108177]
- Shandong Province Higher Educational Science and Technology Program [J16LM02]
- Taishan Scholar Project
Aim: Fusidic acid (FA) is a narrow-spectrum bacteriostatic antibiotic. We inadvertently discovered that a FA derivative modified by an amino-terminal group at the 3-OH position, namely 2, inhibited the growth of Cryptococcus neoformans. Methods & results: Multiscale molecular modeling approaches were used to analyze the binding modes of 2 with eEF2. FA derivatives modified at the 3-OH position were designed based on in silico models; seven derivatives possessing different amino-terminal groups were synthesized and tested in vitro for antifungal activity against C. neoformans. Conclusion: Compound 7 had the strongest minimum inhibitory concentration. Two protonated nitrogen atoms of 7 interacted with a negative electrostatic pocket of eEF2 likely explain the superiority of 7-2. Graphical abstract
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