title: The role of molecular modeling in the design of analogues of the fungicidal natural products crocacins A and D.
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.
authors.affiliation: Syngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire RG426EY, UK. patrick.crowley@syngenta.com
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Crowley
authors.forename: Edward A
authors.initials: EA
authors.lastname: Berry
authors.forename: Thomas
authors.initials: T
authors.lastname: Cromartie
authors.forename: Fevzi
authors.initials: F
authors.lastname: Daldal
authors.forename: Christopher R A
authors.initials: CR
authors.lastname: Godfrey
authors.forename: Dong-Woo
authors.initials: DW
authors.lastname: Lee
authors.forename: Janet E
authors.initials: JE
authors.lastname: Phillips
authors.forename: Anne
authors.initials: A
authors.lastname: Taylor
authors.forename: Russell
authors.initials: R
authors.lastname: Viner
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000577:Amides / Q000737:chemistry*; D000935:Antifungal Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004578:Electron Spin Resonance Spectroscopy; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008928:Mitochondria / Q000187:drug effects; D008956:Models, Chemical; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000475:Alkenes; D000577:Amides; D000935:Antifungal Agents; D009097:Multienzyme Complexes; C500920:crocacin A; C451481:crocacin D; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D014450:Electron Transport Complex III