RESUMO
The zinc metalloprotease neprilysin (NEP) promiscuously degrades small bioactive peptides. NEP is among a select group of metalloenzymes that degrade the amyloid beta-peptide (Aß) in vivo and in situ. Since accumulation of neurotoxic Aß aggregates in the brain appears to be a causative agent in the pathophysiology of Alzheimer's disease (AD), increased clearance of Aß resulting from overexpression of NEP exhibits therapeutic potential for AD. However, higher NEP peptidase activity may be harmful without an increased specificity for Aß over other competing substrates. Crystal structures of NEP-inhibitor complexes and their characterization have highlighted potential amino acid interactions involved in substrate binding and are used as templates to guide our methodology in docking Aß in NEP. Results from protein-ligand docking calculations predict S2' subsite residues Arg 102 and Arg 110 of NEP participate in specific interactions with Aß. These interactions provide insight into developing NEP specificity for Aß.