Discovery of Novel Succinate Dehydrogenase Inhibitors by the Integration of in Silico Library Design and Pharmacophore Mapping

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 rema...

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Bibliographic Details
Published in:Journal of agricultural and food chemistry 2017-04, Vol.65 (15), p.3204-3211
Main Authors: Yao, Ting-Ting, Fang, Shao-Wei, Li, Zhong-Shan, Xiao, Dou-Xin, Cheng, Jing-Li, Ying, Hua-Zhou, Du, Yong-Jun, Zhao, Jin-Hao, Dong, Xiao-Wu
Format: Article
Language:English
Subjects:
Ascomycota - drug effects
Ascomycota - enzymology
Computer Simulation
Drug Design
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Fungal Proteins - antagonists & inhibitors
Fungal Proteins - chemistry
Fungal Proteins - genetics
Fungal Proteins - metabolism
Fungicides, Industrial - chemistry
Fungicides, Industrial - pharmacology
Gene Library
Kinetics
Rhizoctonia - drug effects
Rhizoctonia - enzymology
Succinate Dehydrogenase - antagonists & inhibitors
Succinate Dehydrogenase - chemistry
Succinate Dehydrogenase - genetics
Succinate Dehydrogenase - metabolism
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Summary: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 EC50 values 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.
ISSN:0021-8561
1520-5118
DOI:10.1021/acs.jafc.7b00249