title: Discovery of Novel Succinate Dehydrogenase Inhibitors by the Integration of in Silico Library Design and Pharmacophore Mapping.
abstract: Succinate dehydrogenase (SDH) has been demonstrated as a promising target for fungicide discovery. Crystal structure data have indicated that the carboxyl "core" of current SDH inhibitors contributed largely to their binding affinity. Thus, identifying novel carboxyl "core" SDH inhibitors would remarkably improve the biological potency of current SDHI fungicides. Herein, we report the discovery and optimization of novel carboxyl scaffold SDH inhibitor via the integration of in silico library design and a highly specific amide feature-based pharmacophore model. To our delight, a promising SDH inhibitor, A16c (IC50= 1.07 μM), with a novel pyrazol-benzoic scaffold was identified, which displayed excellent activity against Rhizoctonia solani (EC50= 11.0 μM) and improved potency against Sclerotinia sclerotiorum (EC50= 5.5 μM) and Phyricularia grisea (EC50= 12.0 μM) in comparison with the positive control thifluzamide, with EC50values of 0.09, 33.2, and 33.4 μM, respectively. The results showed that our virtual screening strategy could serve as a powerful tool to accelerate the discovery of novel SDH inhibitors.
authors.affiliation: Institute of Pesticide and Environmental Toxicology, Ministry of Agriculture Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Zhejiang University , Hangzhou 310029, People's Republic of China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Yao
authors.affiliation: Institute of Pesticide and Environmental Toxicology, Ministry of Agriculture Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Zhejiang University , Hangzhou 310029, People's Republic of China.
authors.forename: Shao-Wei
authors.initials: SW
authors.lastname: Fang
authors.affiliation: Institute of Pesticide and Environmental Toxicology, Ministry of Agriculture Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Zhejiang University , Hangzhou 310029, People's Republic of China.
authors.forename: Zhong-Shan
authors.initials: ZS
authors.lastname: Li
authors.affiliation: Institute of Pesticide and Environmental Toxicology, Ministry of Agriculture Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Zhejiang University , Hangzhou 310029, People's Republic of China.
authors.forename: Dou-Xin
authors.initials: DX
authors.lastname: Xiao
authors.affiliation: Institute of Pesticide and Environmental Toxicology, Ministry of Agriculture Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Zhejiang University , Hangzhou 310029, People's Republic of China.
authors.forename: Jing-Li
authors.initials: JL
authors.lastname: Cheng
authors.affiliation: ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, People's Republic of China.
authors.forename: Hua-Zhou
authors.initials: HZ
authors.lastname: Ying
authors.affiliation: Institute of Pesticide and Environmental Toxicology, Ministry of Agriculture Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Zhejiang University , Hangzhou 310029, People's Republic of China.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Du
authors.affiliation: Institute of Pesticide and Environmental Toxicology, Ministry of Agriculture Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Zhejiang University , Hangzhou 310029, People's Republic of China.
authors.forename: Jin-Hao
authors.identifier: http://orcid.org/0000-0002-9198-5399
authors.initials: JH
authors.lastname: Zhao
authors.affiliation: ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, People's Republic of China.
authors.forename: Xiao-Wu
authors.initials: XW
authors.lastname: Dong
mesh_terms: D001203:Ascomycota / Q000187:drug effects / Q000201:enzymology; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005659:Fungicides, Industrial / Q000737:chemistry* / Q000494:pharmacology; D015723:Gene Library; D007700:Kinetics; D012232:Rhizoctonia / Q000187:drug effects / Q000201:enzymology; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D005659:Fungicides, Industrial; D013385:Succinate Dehydrogenase
keywords: amide feature-based pharmacophore model; hit-to-lead optimization; in silico library; molecular modeling; succinate dehydrogenase inhibitors