Screening Hypothesis criticism

Some criticisms of the Screening Hypothesis helped refine the model and the thinking behind the model has since been applied to a wider range of metabolism (see Chapter 9). 

Stereoselective toxicokinetics of pyrethroids was observed in rodents. Rats injected with a racemic dose of 0-cypermethrin had much lower amounts of the (+)-enantiomer compared to the (—)-enantiomer in plasma, heart, liver, kidney, and fat tissues. The authors suggested rapid interconversion of (+)-a5, l/f,35 -cypermethrin to its antipode ( )-a/f,15, 3R-cyper-methrin in plasma, but no reverse conversion of the ( )-enantiomer back to the (+)-enantiomer. This hypothesis was criticized [285] as implausible, as three separate epimer-ization reactions would be necessary for conversion of (+)-a5, l/f,35 -cypermethrin to (—)-a R, 15,3R-cypermethrin. However, the results do indicate significant enantioselectivity in the in vivo processing of cypermethrin by rats, but is not clear to what extent this enantioselectivity was from biotransformation or from tissue-specific redistribution. The latter was suggested by the data [84] consistent with the highly enantioselective screening of a-HCH by the rat blood-brain barrier [259]. 

Virtual screening in the BICLAIM library from our point of view contains five critical steps. First of all, the virtual library needs to include many diverse scaffolds and reagents for a broad decoration. Second, the query has to show high biological activity at the relevant target. Next, all molecules that were identified by the 2D feature tree search are overlaid in 3D with a hypothesis of the bioactive conformation of the query. From these overlays, the crucial selection of the scaffold for synthesis is made. Finally, the decoration of the scaffolds is designed. 

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