摘要
Strobilurin类杀菌剂是继苯并咪唑和三唑类之后杀菌剂研发史上的又一里程碑,靶向线粒体复合物Ⅲ的Qo位点。然而,病原菌对该类杀菌剂抗性问题使得该类杀菌剂的适用收到很大的限制,更为严重的是G143A突变几乎对所有Strobilurin类杀菌剂均产生抗性,因此设计合成新型复合物Ⅲ抑制剂时必须要考虑如何规避G143A突变而导致的抗药性。Pyribencarb是一种新型苄基氨基甲酸酯类杀菌剂,该杀菌剂对灰霉菌和农作物靶点的选择性明显优于已知的Qo位点,最为重要的是C.cassiicola(棒胞菌)的G143A发生突变后对醚菌酯抗性高达600倍,对嘧菌酯更是高达1160多倍,而对Pyribencarb的抗性只有16倍。我们以已有晶体结构为模板采用同源模建的方法构建灰霉菌复合物Ⅲ的三维结构,研究Pyribencarb的结合模式,随后基于该模型进行虚拟筛选以期得到3~4个结构新颖、高活性、抵抗性风险的先导化合物。
The strobilurin fungicides are outstanding new class of cytochrome bc_1 complex Q_o-site inhibitors.However,with strobilurin fungicides being used in a short period of repeated field,significant increases in resistance have been observed especially G143 A in cytochrome b.Therefore,discovering novel inhibitor with high biological activities against resistant pathogens has attracted much attention in recent years.Pyribencarb(Py) is a novel benzylcarbamate-type fungicide active against a wide range of plant pathogenic fungi.For G143 A mutation,strobilurin fungicide-resistant strains were highly resistant to kresoxim-methyl(Kr) and azoxystrobin(Az) but less resistant to Py.So the inhibition mechanism of Py with bc_1complex is very important for rational design and screen the novel inhibitor.Here,the 3D structure of plant pathongenic fungi bc1 complex was built by homology modeling.And then,based on this model,we discussed Py's binding model and it's resistance mechanism for G143 A mutation.
引文
1.Xia,D.;Esser,L.;Tang,W.K.;Zhou,F.;Zhou,Y.;Yu,L.;Yu,C.A.,Biochim Biophys Acta,2013,1827(11-12),1278-94.
2.Fisher,N.;Meunier,B.,FEMS yeast Res,2008,8(2),183-92.
3.Kataoka,S.;Takagaki,M.;Kaku,K.;Shimizu,T.,J PEST SCI,2010,35(2),99-106.