Discovery of Potent Succinate-Ubiquinone Oxidoreductase Inhibitors via Pharmacophore-linked Fragment Virtual Screening Approach

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• 作者：Li Xiong ; Xiao-Lei Zhu ; Hua-Wei Gao ; Yu Fu ; Sheng-Quan Hu ; Li-Na Jiang ; Wen-Chao Yang ; Guang-Fu Yang
• 刊名：Journal of Agricultural and Food Chemistry
• 出版年：2016
• 出版时间：June 22, 2016
• 年：2016
• 卷：64
• 期：24
• 页码：4830-4837
• 全文大小：399K
• 年卷期：0
• ISSN：1520-5118

文摘

Succinate-ubiquinone oxidoreductase (SQR) is an attractive target for fungicide discovery. Herein, we report the discovery of novel SQR inhibitors using a pharmacophore-linked fragment virtual screening approach, a new drug design method developed in our laboratory. Among newly designed compounds, compound 9s was identified as the most potent inhibitor with a K_i value of 34 nM against porcine SQR, displaying approximately 10-fold higher potency than that of the commercial control penthiopyrad. Further inhibitory kinetics studies revealed that compound 9s is a noncompetitive inhibitor with respect to the substrate cytochrome c and DCIP. Interestingly, compounds 8a, 9h, 9j, and 9k exhibited good in vivo preventive effects against Rhizoctonia solani. The results obtained from molecular modeling showed that the orientation of the R² group had a significant effect on binding with the protein.