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

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.