Ametoctradin is a potent Qo site inhibitor of the mitochondrial respiration complex III

Journal of Agricultural and Food Chemistry
Xiao-Lei ZhuGuang-Fu Yang

Abstract

Ametoctradin is a new Oomycete-specific fungicide under development by BASF. It is a potent inhibitor of the bc1 complex in mitochondrial respiration. However, its detailed action mechanism remains unknown. In the present work, the binding mode of ametoctradin was first uncovered by integrating molecular docking, MD simulations, and MM/PBSA calculations, which showed that ametoctradin should be a Q(o) site inhibitor of bc1 complex. Subsequently, a series of new 1,2,4-triazolo[1,5-a]pyrimidine derivatives were designed and synthesized to further understand the substituent effects on the 5- and 6-position of 1,2,4-triazolo[1,5-a]pyrimidine. The calculated binding free energies (ΔG(cal)) of newly synthesized analogues as Qo site inhibitors correlated very well (R(2) = 0.96) with their experimental binding free energies (ΔG(exp)). Two compounds (4a and 4c) with higher inhibitory activity against porcine SQR than ametoctradin were successfully identified. The structural and mechanistic insights obtained from the present study will provide a valuable clue for future designing of a new promising bc1 inhibitor.

References

Sep 18, 2002·Pest Management Science·Ulrich GisiAlan McCaffery
Nov 25, 2003·FEBS Letters·Edward A Berry, Li-shar Huang
Dec 13, 2003·The Journal of Biological Chemistry·Emma Berta Gutierrez-CirlosBernard L Trumpower
Feb 14, 2012·Journal of Chemical Theory and Computation·Ayşegül OzenCelia A Schiffer

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Citations

Jul 16, 2016·Angewandte Chemie·Kensuke KiyokawaSatoshi Minakata
Jan 26, 2018·Frontiers in Molecular Biosciences·Changhao WangRay Luo
Mar 30, 2021·Journal of Agricultural and Food Chemistry·Ge WeiGuang-Fu Yang
Feb 23, 2019·Journal of Agricultural and Food Chemistry·Xiao-Lei ZhuGuang-Fu Yang
Dec 16, 2020·The Journal of Organic Chemistry·Ge ZengRenhao Li

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