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Rational Design of Highly Potent and Slow-Binding Cytochrome bc 1 Inhibitor as Fungicide by Computational Substitution Optimization

Scientific Reports, ISSN: 2045-2322, Vol: 5, Issue: 1, Page: 13471
2015
  • 16
    Citations
  • 0
    Usage
  • 23
    Captures
  • 0
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    16
    • Citation Indexes
      16
  • Captures
    23

Article Description

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 bc 1 complex, ∼73-fold more potent (K i = 4.1 nM) than the best commercial fungicide azoxystrobin (AZ; K i = 97.6 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.

Bibliographic Details

Ge Fei Hao; Sheng Gang Yang; Wei Huang; Yan Qing Shen; Wen Long Tu; Hui Li; Guang Fu Yang; Le Wang; Jia Wei Wu; Li Shar Huang; Edward A. Berry

Springer Science and Business Media LLC

Multidisciplinary

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