Halogen bond interactions for design of Trypanosoma cruzi inhibitors

BOGADO M.L; LUCHI A.M; GÓMEZ CHÁVEZ JOSÉ LEONARDO; DUARTE D.J.R

Ciudad Autónoma Buenos Aires

Congreso; DRUG DISCOVERY FOR NEGLECTED DISEASES INTERNATIONAL CONGRESS 2018; 2018

CONICET, IQUIMEFA, Universidad de Buenos Aires

Chagas disease is a trypanosomiasis caused by the protozoan parasite Trypanosoma cruzi. Millions of people areaffected in Latin America where the disease is associated with high mortality. With the hope of identifying moresafety drugs and with selective antichagasic effect, the interest has been directed to parasitic proteases as possiblepharmacological targets, being Cruzipain (Cz) the main cysteine protease in T. cruzi.In this work we studied the halogen bonds (EX) established by halogenated ligands (LX) in the Cz binding pocket byMolecular Dynamics (DM) simulations and topological analysis of the electronic density.Our strategy to uncover the importance of EX for Cz inhibition was to contrast its properties with those of thecorresponding EHs formed by less active non-halogenated analogs (LH) in which halogen was replaced by an hydrogenatom.The starting point for this study was the knowledge of the three-dimensional structure of Cz bound non-covalentlyto the brominated ligand B95 (N- [2- (1H-benzimidazol-2-yl) ethyl] -2- (2-bromophenoxy) acetamide) where bromineforms an EX with the sulfur atom from methionine residue Met68. Interestingly, the corresponding LH, has an activity14 times lower than its LX counterpart. Similarly, the naphthoxy-B95 derivative exhibits an activity 15 times greaterthan its LH counterpart.To figure out the origin of activity differences in the LX / LH pairs, DM simulations were performed using the AMBERprogram package. To simulate the σ-hole on the halogen atom, an extra-point (EP) with a positive charge and withoutmass was introduced into the Amber force field. The parametrization of the EP was carried out following the procedureof Ibrahim, the C (ar)-X-EP angle was established at 180 ° and the X -EP distance was set to bromine atomic radius(2.22 Å). The atomic partial charges were assigned by the restricted electrostatic potential (RESP) method. Finally, once the DM trajectories for the complexes were obtained, the intermolecular interactions were evaluated by applyingQTAIM methodology [5] on reduced model systems of both complexes.In this work the EX interactions formed by brominated ligands with activity annotations against Cz were studied. Thestructural as well as the QTAIM analysis revealed differences in the interaction patterns, the results show that while theLX is able to maintain the interaction with Met68 as in the solved structure, the LH counterpart early detaches from Czbinding pocket.