Discovery of novel non-competitive inhibitors of mammalian neutral M1 aminopeptidase (APN).

ABSTRACT: Neutral metallo-aminopeptidase (APN) catalyzes the cleavage of neutral and basic amino acids from the N-terminus of protein or peptide substrates. APN expression is dysregulated in inflammatory diseases as well as in several types of cancer. Therefore, inhibitors of APN may be effective against cancer and inflammation. By virtual screening and enzymatic assays, we identified three non-competitive inhibitors (α > 1) of the porcine and human APN with K_i values in the μM range. These non-peptidic compounds lack the classical zinc-binding groups (ZBG) present in most of the APN inhibitors. Molecular docking simulations suggested the novel inhibitors suppress APN activity by an alternative mechanism to Zn coordination: they interacted with residues comprising the S1 and S5' subsites

SUBMITTER: Pascual I 

PROVIDER: S-EPMC7127808 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature