Network analysis in complex Protein-Inhibitor systems: a Cruzain case study

Abstract

Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. Cruzain (Cz), the parasite major cysteine-protease, is a viable target for developing new drugs. A survey on public databases with activity annotations revealed that several Cz inhibitors containing a halogen atom (LX, X = Cl, Br, I) were up to thousands of times more active than their non-halogenated analogs (LH) giving rise to an activity cliff in the Cz/inhibitor interaction landscape. On the other hand, structural evidence indicates that halogenated compounds form an X···S halogen bond (XB) with Methionine 68 (PDB ID 3KKU). These findings altogether suggest that XB formation could induce disruptive changes within the protein structure.