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We hypothesize that (i) the slow inhibition observed in the biochemical assay with the recombinant protein with some of the compounds is due to their preferential binding to a slowly populated conformer of the NADP + -TGR(H) complex and (ii) this conformer is already populated in the worm cell interior accounting for the more rapid inhibition of TGR observed in ex vivo worms with the slow inhibitors

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Phentermine is the opposite on this point: it reaches its peak concentration within a few hours and clears quickly, which fits its role as a short-term push