Journal of Pharmaceutical Chemistry & Chemical Science

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Journal of Pharmaceutical Chemistry & Chemical Science 44 7897 074717

Scholarly Journal Of New Chemical Entities

This work presents the validation of a rapid screening procedure for the catalysis of cytochrome P450 on new chemical entities. The assay is tested on the prototypical, catalytically self-sufficient and soluble cytochrome P450 BM3 from Bacillus megaterium that shares a high degree of homology with mammalian counterparts. The so-called alkali assay developed in our laboratory is validated here also by product formation and molecular modeling on variety of derivatives sharing the molecular scaffold of the 1,2,5-oxadiazole ring, a category of molecules very different from the long-chain fatty acids known to be oxidized by cytochrome P450 BM3. The alkali assay reveals the power of this cytochrome to oxidize NADPH within the presence of nine out of thirteen 1,2,5-oxadiazole derivatives tested. The enzyme shows high affinity and coupling efficiencies when incubated with four 1,2,5-oxadiazole derivatives. The presence of oxidation products deriving from catalysis was also confirmed by high-performance liquid chromatography (HPLC). Molecular docking suggests that a key factor for the 1,2,5-oxadiazole derivatives to enter the site and induce catalysis is that the presence of the –SO2 moiety bridging the 1,2,5-oxadiazole and phenyl rings. These data indicate that the alkali assay is in a position to quickly and cheaply detect the popularity of latest substrates by cytochrome P450. The assay isn't intended to substitute HPLC–mass spectrometry analysis, but it's a preliminary screening that permits elimination of obvious nonsubstrates from the beginning .

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