A structural insight into the P1S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases.

摘要: N'-substituted 1,2-diaminoethylphosphonic acids and 1,2-diaminoethylphosphinic dipeptides were explored to unveil the structural context of unexpected selectivity these inhibitors M1 alanine aminopeptidases (APNs) versus M17 leucine aminopeptidase (LAP). The diaminophosphonic obtained via aziridines in an improved synthetic procedure that was further expanded for phosphinic pseudodipeptide system. inhibitory activity, measured three one metalloaminopeptidases different sources (bacterial, human porcine), revealed several potent compounds (e.g., Ki = 65 nM 1u HsAPN). Two structures representative (APN from Neisseria meningitidis) complex with N-benzyl-1,2-diaminoethylphosphonic acid N-cyclohexyl-1,2-diaminoethylphosphonic determined by X-ray crystallography. analysis models phosphonic complexes ortholog provided insight into role additional amino group hydrophobic substituents ligands within S1 active site region.