Enantiomer Discrimination Illustrated by the High Resolution Crystal Structures of Type 4 Phosphodiesterase

摘要

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,IC_(50)=0.4 nM) and its enantiomer (-)-1 (L-869299,IC_(50)=43 nM) and their cocrystal structures with PDE4D at 2.0 A 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.