Discovery of Potent Succinate-Ubiquinone Oxidoreductase Inhibitors via Pharmacophore-linked Fragment Virtual Screening Approach.
Discovery of Potent Succinate-Ubiquinone Oxidoreductase Inhibitors via Pharmacophore-linked Fragment Virtual Screening Approach.
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DOI：
10.1021/acs.jafc.6b00325
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发表时间：
2016-06
影响因子：
6.1
通讯作者：
Li Xiong;Xiao-Lei Zhu;Hua Gao;Yunshuang Fu;Sheng-quan Hu;Lina Jiang;Wenchao Yang;Guangfu Yang
中科院分区：
文献类型：
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作者：
Li Xiong;Xiao-Lei Zhu;Hua Gao;Yunshuang Fu;Sheng-quan Hu;Lina Jiang;Wenchao Yang;Guangfu Yang
琥珀酸泛醌氧化还原酶（SQR）是一个有吸引力的目标杀菌剂发现。在此，我们报告了新的SQR抑制剂的发现，使用药效团连接的片段虚拟筛选方法，在我们的实验室开发的一种新的药物设计方法。在新设计的化合物中，化合物9s被鉴定为最有效的抑制剂，其对猪SQR的Ki值为34 nM，显示出比商业对照吡噻菌胺高约10倍的效力。进一步的抑制动力学研究表明，化合物9s对底物细胞色素c和DCIP是一种非竞争性抑制剂。有趣的是，化合物8a、9h、9j和9k对立枯丝核菌表现出良好的体内预防效果。从分子模拟获得的结果表明，R（2）基团的方向对与蛋白质的结合有显着的影响。
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 Ki 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 R(2) group had a significant effect on binding with the protein.