Charge Density as a Molecular Descriptor to Unravel Structure-Activity Relationships of Cruzain Inhibitors

Abstract

Chagas disease is endemic to South and Central America caused by the parasite Tripanosoma cruzi. Actually just two drugs like nifurtimox and benznidazole are available, however they are highly toxic and drug resistance has been reported. Cruzain (Cz), the major cysteine protease of T. cruzi, is one attractive drug target; since, it is required for all the major proteolytic activities of the parasite life circle. Cysteine protease inhibitors containing a vinyl sulfone warhead can exhibit good selectivity and a favorable in vivo safety profile despite the irreversible nature of inhibition. K-777, a vinyl sulfone inhibitor of Cz has shown to be safe and efficacious in animal models of acute and chronic Chagas disease but the project was stopped due to tolerability issues at low dose in primates and dogs.Jaishankar et al. synthesized and determined the inhibition constant of a series of vinyl sulfone ana-logs closely related to K-777 with substitutions at P2 and P3. Unfortunately, 3-D structures of these complexes are not available yet. However, there are several solved structures of Cz complexed with vinyl sulfone analogs available in the PDB. Moreover, all these irreversible inhibitors mimic the well known binding mode of classical substrate-like peptidic inhibitors. This structural information allowed us to make a reasonably good initial guess of the binding mode of these K-777 analogues at the Cz active site. Complexes were then subjected to MD simulations. Reduced model systems comprising inhibitor and residues from the Cz binding pocket were constructed from the MD simu-lation. Charge density topological analysis based in QTAIM was performed on these reduced models to evaluate the inhibitor/Cz interactions. By carefully inspecting the electron density values at the interactions bond critical points, we found out what are the key interactions that explain the activity differences (Ki values) among K-777 analogues.