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

doi:10.1016/j.bmc.2008.10.030

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

Department of Biotechnology

Research output: Contribution to journal › Article

33 Citations (Scopus)

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 bc₁ 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 bc₁ complex, which validated the binding model and which confirmed that the crocacins are a new class of inhibitor of the cytochrome bc₁ complex.

Original language	English
Pages (from-to)	10345-10355
Number of pages	11
Journal	Bioorganic and Medicinal Chemistry
Volume	16
Issue number	24
DOIs	https://doi.org/10.1016/j.bmc.2008.10.030
Publication status	Published - 2008 Dec 15

All Science Journal Classification (ASJC) codes

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

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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

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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 bc1 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 bc1 complex, which validated the binding model and which confirmed that the crocacins are a new class of inhibitor of the cytochrome bc1 complex.",

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The role of molecular modeling in the design of analogues of the fungicidal natural products crocacins A and D. / Crowley, Patrick J.; Berry, Edward A.; Cromartie, Thomas; Daldal, Fevzi; Godfrey, Christopher R.A.; Lee, Dong Woo; Phillips, Janet E.; Taylor, Anne; Viner, Russell.

In: Bioorganic and Medicinal Chemistry, Vol. 16, No. 24, 15.12.2008, p. 10345-10355.

Research output: Contribution to journal › Article

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