Journal
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
Volume 65, Issue 15, Pages 3204-3211Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jafc.7b00249
Keywords
succinate dehydrogenase inhibitors; in silico library; amide feature-based pharmacophore model; hit-to-lead optimization; molecular modeling
Funding
- National Key Research and Development Program of China [2016YFD0200804]
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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 mu M), with a novel pyrazol-benzoic scaffold was identified, which displayed excellent activity against Rhizoctonia solani (EC50 = 11.0 mu M) and improved potency against Sclerotinia sclerotiorum (EC50 = 5.5 mu M) and Phyricularia grisea (EC50 = 12.0 mu M) in comparison with the positive control thifluzamide, with ECso values of 0.09, 33.2, and 33.4 mu M, respectively. The results showed that our virtual screening strategy could serve as a powerful tool to accelerate the discovery of novel SDH inhibitors.
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