1. Rational Design of Highly Potent and Slow-Binding Cytochrome bc1 Inhibitor as Fungicide by Computational Substitution Optimization.
- Author
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Hao, Ge-Fei, Yang, Sheng-Gang, Huang, Wei, Wang, Le, Shen, Yan-Qing, Tu, Wen-Long, Li, Hui, Huang, Li-Shar, Wu, Jia-Wei, Berry, Edward A., and Yang, Guang-Fu
- Subjects
AGRICULTURAL chemicals ,CYTOCHROMES ,FUNGICIDES ,AZOXYSTROBIN ,CRYSTALLOGRAPHY ,LIGANDS (Biochemistry) - Abstract
Hit to lead (H2L) optimization is a key step for drug and agrochemical discovery. A critical challenge for H2L optimization is the low efficiency due to the lack of predictive method with high accuracy. We described a new computational method called Computational Substitution Optimization (CSO) that has allowed us to rapidly identify compounds with cytochrome bc
1 complex inhibitory activity in the nanomolar and subnanomolar range. The comprehensively optimized candidate has proved to be a slow binding inhibitor of bc1 complex, ~73-fold more potent (Ki = 4.1 nM) than the best commercial fungicide azoxystrobin (AZ; Ki = 297.6 nM) and shows excellent in vivo fungicidal activity against downy mildew and powdery mildew disease. The excellent correlation between experimental and calculated binding free-energy shifts together with further crystallographic analysis confirmed the prediction accuracy of CSO method. To the best of our knowledge, CSO is a new computational approach to substitution-scanning mutagenesis of ligand and could be used as a general strategy of H2L optimisation in drug and agrochemical design. [ABSTRACT FROM AUTHOR]- Published
- 2015
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