title: Ametoctradin is a potent Qo site inhibitor of the mitochondrial respiration complex III.
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.
authors.affiliation: †Key Laboratory of Pesticide and Chemical Biology, College of Chemistry, Ministry of Education, Central China Normal University, Wuhan 430079, P.R. China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: †Key Laboratory of Pesticide and Chemical Biology, College of Chemistry, Ministry of Education, Central China Normal University, Wuhan 430079, P.R. China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: †Key Laboratory of Pesticide and Chemical Biology, College of Chemistry, Ministry of Education, Central China Normal University, Wuhan 430079, P.R. China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liu
authors.affiliation: †Key Laboratory of Pesticide and Chemical Biology, College of Chemistry, Ministry of Education, Central China Normal University, Wuhan 430079, P.R. China.
authors.forename: Jingming
authors.initials: J
authors.lastname: Ge
authors.affiliation: †Key Laboratory of Pesticide and Chemical Biology, College of Chemistry, Ministry of Education, Central China Normal University, Wuhan 430079, P.R. China.|‡Collaborative Innovation Center of Chemical Science and Engineering, Tianjing 30071, P.R.China.
authors.forename: Guangfu
authors.initials: G
authors.lastname: Yang
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005659:Fungicides, Industrial / Q000138:chemical synthesis / Q000494:pharmacology*; D008928:Mitochondria / Q000737:chemistry*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009868:Oomycetes / Q000187:drug effects; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013552:Swine; D013816:Thermodynamics; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D005659:Fungicides, Industrial; D011743:Pyrimidines; D014230:Triazoles; D014450:Electron Transport Complex III; C000601857:ametoctradin
keywords: ametoctradin; cytochrome bc1 complex; molecular docking; molecular dynamics