The role of molecular modeling in the design of analogues of the fungicidal natural products crocacins A and D

Patrick J. Crowley, Edward A. Berry, Thomas Cromartie, Fevzi Daldal, Christopher R.A. Godfrey, Dong Woo Lee, Janet E. Phillips, Anne Taylor, Russell Viner

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Abstract

Extensive molecular modeling based on crystallographic data was used to aid the design of synthetic analogues of the fungicidal naturally occurring respiration inhibitors crocacins A and D, and an inhibitor binding model to the mammalian cytochrome bc 1 complex was constructed. Simplified analogues were made which showed high activity in a mitochondrial beef heart respiration assay, and which were also active against certain plant pathogens in glasshouse tests. A crystal structure was obtained of an analogue of crocacin D bound to the chicken heart cytochrome bc 1 complex, which validated the binding model and which confirmed that the crocacins are a new class of inhibitor of the cytochrome bc 1 complex.

Original languageEnglish
Pages (from-to)10345-10355
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number24
DOIs
Publication statusPublished - 2008 Dec 15

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Crowley, P. J., Berry, E. A., Cromartie, T., Daldal, F., Godfrey, C. R. A., Lee, D. W., Phillips, J. E., Taylor, A., & Viner, R. (2008). The role of molecular modeling in the design of analogues of the fungicidal natural products crocacins A and D. Bioorganic and Medicinal Chemistry, 16(24), 10345-10355. https://doi.org/10.1016/j.bmc.2008.10.030