title: Discovery of Potent Succinate-Ubiquinone Oxidoreductase Inhibitors via Pharmacophore-linked Fragment Virtual Screening Approach.
abstract: Succinate-ubiquinone oxidoreductase (SQR) is an attractive target for fungicide discovery. Herein, we report the discovery of novel SQR inhibitors using a pharmacophore-linked fragment virtual screening approach, a new drug design method developed in our laboratory. Among newly designed compounds, compound 9s was identified as the most potent inhibitor with a Ki value of 34 nM against porcine SQR, displaying approximately 10-fold higher potency than that of the commercial control penthiopyrad. Further inhibitory kinetics studies revealed that compound 9s is a noncompetitive inhibitor with respect to the substrate cytochrome c and DCIP. Interestingly, compounds 8a, 9h, 9j, and 9k exhibited good in vivo preventive effects against Rhizoctonia solani. The results obtained from molecular modeling showed that the orientation of the R(2) group had a significant effect on binding with the protein.
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, P.R. China.
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, P.R. China.
authors.forename: Hua-Wei
authors.initials: HW
authors.lastname: Gao
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, P.R. China.
authors.forename: Sheng-Quan
authors.initials: SQ
authors.lastname: Hu
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, P.R. China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, P.R. China.
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Yang
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, P.R. China.|Collaborative Innovation Center of Chemical Science and Engineering , Tianjin 30071, P.R.China.
authors.forename: Guang-Fu
authors.initials: GF
authors.lastname: Yang
mesh_terms: D055808:Drug Discovery; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects; D005659:Fungicides, Industrial / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D019802:Succinic Acid
chemical_list: D004791:Enzyme Inhibitors; D005659:Fungicides, Industrial; D019802:Succinic Acid; D042963:Electron Transport Complex II
keywords: complex II; molecular modeling; pharmacophore-linked fragment virtual screening; structure-based design; succinate-ubiquinone oxidoreductase