CHARGE DENSITY AS A MOLECULAR DESCRIPTOR TO UNRAVEL STRUCTURE-ACTIVITY RELATIONSHIPS OF CRUZAIN INHIBITORS

LUCHI, ADRIANO MARTIN; RAMIREZ, ANGEL; BOGADO, MARIA LUCRECIA; ANGELINA, EMILIO ; PERUCHENA, NELIDA

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Chagas disease is endemic to South and Central Americacaused by the parasite Tripanosoma cruzi. Actually just twodrugs like nifurtimox and benznidazole are available, howev-er they are highly toxic and drug resistance has been report-ed. Cruzain (Cz), the major cysteine protease of T. cruzi, isone attractive drug target; since, it is required for all the majorproteolytic activities of the parasite life circle.Cysteine protease inhibitors containing a vinyl sulfone war-head can exhibit good selectivity and a favorable in vivosafety profile despite the irreversible nature of inhibition.K-777, a vinyl sulfone inhibitor of Cz has shown to be safeand efficacious in animal models of acute and chronic Cha-gas disease but the project was stopped due to tolerabilityissues at low dose in primates and dogs.Jaishankar et al. synthesized and determined the inhibitionconstant of a series of vinyl sulfone analogs closely relatedto K-777 with substitutions at P2 and P3. Unfortunately, 3-Dstructures of these complexes are not available yet. How-ever, there are several solved structures of Cz complexedwith vinyl sulfone analogs available in the PDB. Moreover,all these irreversible inhibitors mimic the well known bind-ing mode of classical substrate-like peptidic inhibitors. Thisstructural information allowed us to make a reasonably goodinitial guess of the binding mode of these K-777 analoguesat the Cz active site. Complexes were then subjected to MDsimulations. Reduced model systems comprising inhibitorand residues from the Cz binding pocket were constructedfrom the MD simulation. Charge density topological analysisbased in QTAIM was performed on these reduced models toevaluate the inhibitor/Cz interactions.By carefully inspecting the electron density values at the in-teractions bond critical points, we found out what are thekey interactions that explain the activity differences (Ki val-ues) among K-777 analogues.