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

VILLAFAÑE, ROXANA NOELIA; BOGADO, MARIA LUCRECIA; ANGELINA, EMILIO LUIS; PERUCHENA, NÉLIDA MARIA

Congreso; 1st Latin American Congress of Women in Bioinformatics & Data Science; 2020

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.Network analysis has been used extensively to study allosterism in proteins, but coupled with molecular dynamics (MD) becomes an invaluable tool to study conformational changes and flexibility regions in proteins. Four pairs of LX/LH inhibitors from the thiosemicarbazone family that met these ?activity cliff? characteristics were compiled and subjected to Docking calculations followed by MD simulations. Through the Network Analysis, it was found that the integrity of the network associated with the halogenated complexes is particularly affected by the loss of communication between two specific regions of Cz, which induces conformational changes that could enhance complex stability. The loss of communication was revealed by pathway analysis showing that XBs have longer paths along with the selected residues from S2 sub-pocket and other important sites of the protein. These results provide some clues about how XBs can be exploited to design more potent Cz inhibitors.