The role of molecular modeling in the design of analogues of the fungicidal natural products crocacins A and D.
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.
Crowley
Patrick J
PJ
Syngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire RG426EY, UK. patrick.crowley@syngenta.com
Berry
Edward A
EA
Cromartie
Thomas
T
Daldal
Fevzi
F
Godfrey
Christopher R A
CR
Lee
Dong-Woo
DW
Phillips
Janet E
JE
Taylor
Anne
A
Viner
Russell
R
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
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