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- W1979900960 abstract "Type 4 phosphodiesterase (PDE4) inhibitors are emerging as new treatments for a number of disorders including asthma and chronic obstructive pulmonary disease. Here we report the biochemical characterization on the second generation inhibitor (+)-1 (L-869298, IC50 = 0.4 nM) and its enantiomer (−)-1 (L-869299, IC50 = 43 nM) and their cocrystal structures with PDE4D at 2.0 Å resolution. Despite the 107-fold affinity difference, both enantiomers interact with the same sets of residues in the rigid active site. The weaker (−)-1 adopts an unfavorable conformation to preserve the pivotal interactions between the Mg-bound waters and the N-oxide of pyridine. These structures support a model in which inhibitors are anchored by the invariant glutamine at one end and the metal-pocket residues at another end. This model provides explanations for most of the observed structure−activity relationship and the metal ion dependency of the catechol-ether based inhibitors and should facilitate their further design." @default.
- W1979900960 created "2016-06-24" @default.
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- W1979900960 date "2006-03-01" @default.
- W1979900960 modified "2023-10-15" @default.
- W1979900960 title "Enantiomer Discrimination Illustrated by the High Resolution Crystal Structures of Type 4 Phosphodiesterase" @default.
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- W1979900960 doi "https://doi.org/10.1021/jm051273d" @default.
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