Abstract
Quinone outside inhibitors (QoIs), which inhibit the mitochondrial respiratory system by binding to the Qo site of Complex III in fungi, are widely used as pesticides with broad spectrum antifungal activity. However, excessive use of QoIs leads to pesticide resistance through mutation of amino acid residues in the Qo site. Recently, metyltetraprole, a novel QoI that is effective against wild-type and resistant mutant fungi, was developed. Interestingly, metyltetraprole has a very similar structure to other QoIs, azoxystrobin and pyraclostrobin, which do not act on resistant mutants. However, it is unknown how slight structural differences in these inhibitors alter their effectiveness towards fungi with amino acid mutations in the Qo site of Complex III. Therefore, we studied the features of interactions of inhibitors effective towards resistant mutants by quantitatively comparing the interaction profiles of three QoIs at the atomic level. First, we reproduced the binding affinity by the thermodynamic integration (TI) method, which treated explicitly environmental molecules and considered the pseudo-binding pathway. As such, a good correlation (R2 = 0.74) was observed between the binding free energy calculated using the TI method and experimentally observed pIC50 value in 12 inhibitor-target pairs, including wild-type and mutant Complex III in two fungal species, Zymoseptoria tritici and Pyrenophora teres. Trajectory analysis of this TI calculation revealed that the effectiveness against resistant mutant fungi strongly depended on the interaction of constituent parts of the inhibitor disposed near the active center of the target protein. Specifically, the key in the effectiveness against resistant mutant fungi is that the corresponding component part, tetrazolinone moiety of metyltetraprole, traded off Coulomb and van der Waals interactions in response to subtle changes in the binding pose.
Highlights
Since the global population has been predicted to grow, a stable supply of grain is important
One is to judge whether the constructed simulation system is valid or not, and the other is to judge whether the calculation of binding free energy, which is the step, is performed correctly
It was revealed that metyltetraprole is a unique quinone outside inhibitors (QoI) distinct from existing inhibitors due to its interaction with the target
Summary
Since the global population has been predicted to grow, a stable supply of grain is important. One of the factors that limit the stable supply of grains is plant disease, which decreases yield and quality. Various fungicides have been developed and used worldwide to control pathogenic fungi. Control measures dependent on certain fungicides can lead to increase in resistant fungi and significantly reduce effectiveness of fungicides. To avoid this situation, countermeasures have been applied to use cyclically or mix multiple disinfectants with different mechanisms of action [1]. Fungicides with a broad action spectrum are intensively used because multiple diseases occur simultaneously in practical situations. Three classes of fungicides, sterol biosynthesis inhibitors, quinone outside inhibitors (QoI), and succinate dehydrogenase inhibitors exceeded 60% of the disinfectant sales shares in 2016 [2]
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