杀菌剂
机制(生物学)
化学
细胞色素c
细胞色素
立体化学
生物物理学
生物化学
生物
植物
线粒体
酶
物理
量子力学
作者
Ying Dong,Bo Li,Min Yin,Zheng Liu,Yan D. Niu,Qiong‐You Wu,Xiaolei Zhu,Guang‐Fu Yang
标识
DOI:10.1021/acs.jafc.3c05982
摘要
Picolinamide fungicides, structurally related to UK-2A and antimycin-A, bind into the Qi-site in the bc1 complex. However, the detailed binding mode of picolinamide fungicides remains unknown. In the present study, antimycin-A and UK-2A were selected to study the binding mode of picolinamide inhibitors with four protonation states in the Qi-site by integrating molecular dynamics simulation, molecular docking, and molecular mechanics Generalized Born surface area (MM/GBSA) calculations. Subsequently, a series of new picolinamide derivatives were designed and synthesized to further understand the effects of substituents on the tail phenyl ring. The computational results indicated that the substituted aromatic rings in antimycin-A and UK-2A were the pharmacophore fragments and made the primary contribution when bound to a protein. Compound 9g-hydrolysis formed H-bonds with Hie201 and Ash228 and showed an IC50 value of 6.05 ± 0.24 μM against the porcine bc1 complex. Compound 9c, with a simpler chemical structure, showed higher control effects than florylpicoxamid against cucumber downy mildew and expanded the fungicidal spectrum of picolinamide fungicides. The structural and mechanistic insights obtained from the present study will provide a valuable clue for the future designing of new promising Qi-site inhibitors.
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