Structure-based design of inhibitors of the rice blast fungal enzyme trihydroxynaphthalene reductase

Douglas B. Jordan, Gregory S. Basarab, Der Ing Liao, Wynona M P Johnson, Kevin N. Winzenberg, David A. Winkler

Research output: Contribution to journalArticleOther

34 Citations (Scopus)

Abstract

Rice Blast Disease, caused by the fungus Pyricularia oryzae, is one of the most important diseases of rice. Several enzymes in the melanin biosynthetic pathway have proven to be valuable targets for development of rice blast fungicides. In particular, inhibitors of trihydroxynaphthalene reductase (3HNR), which catalyzes the conversion of trihydroxynaphthalene to vermelone, have yielded commercially useful rice fungicides. The X-ray structure of 3HNR has been published recently, presenting an opportunity to use this information in the de novo design of novel 3HNR inhibitors that may exhibit useful rice blast activity. We used the LeapFrog program to develop a docking model for interaction of ligands with the active site of THNR. The final model gave a good correlation between calculated binding energy and log Ki and was used to design novel ligands and score compounds for synthesis. Using this as a tool, we synthesized inhibitors in the nanomolar range and also developed several inhibitors that did not conform to the properties of the THNR active site. Leapfrog was able to locate a previously unrecognized binding pocket that could accommodate these otherwise anomalous regions of structure. 

Original languageEnglish
Pages (from-to)434-447
Number of pages14
JournalJournal of Molecular Graphics and Modelling
Volume19
Issue number5
DOIs
Publication statusPublished - 2001
Externally publishedYes

Keywords

  • De novo design
  • Enzyme inhibitors
  • Fungicides
  • LeapFrog
  • Rice blast
  • Trihydroxynaphthalene reductase

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