Drug targeting of aminopeptidases: importance of deploying a right metal cofactor

Aminopeptidases are metal co-factor-dependent hydrolases releasing N-terminal amino acid residues from peptides. Many of these enzymes, particularly the M24 methionine aminopeptidases (MetAPs), are considered valid drug targets in the fight against many parasitic and non-parasitic diseases. Targeting MetAPs has shown promising results against the malarial parasite, Plasmodium, which is regarded as potential anti-cancer targets. While targeting these essential enzymes represents a potentially promising approach, many challenges are often ignored by scientists when designing drugs or inhibitory scaffolds against the MetAPs. One such aspect is the metal co-factor, with inadequate attention paid to its role in catalysis, folding and remodeling of the catalytic site, and its role in inhibitor binding or potency. Knowing that a metal co-factor is essential for aminopeptidase enzyme activity and active site remodeling, it is intriguing that most computational biologists often ignore the metal ion while screening millions of potential inhibitors to find hits. Ironically, a similar trend is followed by biologists who avoid metal promiscuity of these enzymes while screening inhibitor libraries in vitro which may lead to false positives. This review highlights the importance of considering a physiologically relevant metal co-factor during the drug discovery processes targeting metal-dependent aminopeptidases.