HALOGEN BOND INTERACTIONS FOR DESIGN OF Trypanosome cruzi INHIBITORS

LUCHI, ADRIANO M.; SOSA, GLADIS LAURA; BOGADO, LUCRECIA; DUARTE, DARIO J. R.; PERUCHENA, N. M.; PEREZ CHAVEZ, J.L.; ANGELINA, EMILIO

BUENOS AIRES

Congreso; Drug Discovery for Neglected Diseases International Congress 2018 4th Scientific Meeting of ResNet NPND.; 2018

IQUIMEFA (CONICET-UBA) ResNet NPND.

Chagas disease is a trypanosomiasis caused by the protozoan parasite Trypanosoma cruzi. Millions of people are affected in Latin America where the disease is associated with high mortality. With the hope of identifying more safety drugs and with selective antichagasic effect, the interest has been directed to parasitic proteases as possible pharmacological targets, being Cruzipain (Cz) the main cysteine protease in T. cruzi. [1]In this work we studied the halogen bonds (EX) established by halogenated ligands (LX) in the Cz binding pocket by Molecular 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 the corresponding EHs formed by less active non halogenated analogs (LH) in which halogen was replaced by an hydrogen atom.The starting point for this study was the knowledge of the three-dimensional structure of Cz bound non-covalently to the brominated ligand B95 (N- [2- (1H-benzimidazol-2-yl) ethyl] -2- (2-bromophenoxy) acetamide) where bromine forms an EX with the sulfur atom from methionine residue Met68. Interestingly, the corresponding LH, has an activity 14 times lower than its LX counterpart [2]. Similarly, the naphthoxy-B95 derivative exhibits an activity 15 times greater than its LH counterpart.To figure out the origin of activity differences in the LX / LH pairs, DM simulations were performed using the AMBER program package [3]. To simulate the σ-hole on the halogen atom, an extra-point (EP) with a positive charge and without mass was introduced into the Amber force field. The parametrization of the EP was carried out following the procedure of Ibrahim [4], 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 applying QTAIM 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. The structural as well as the QTAIM analysis revealed differences in the interaction patterns, the results show that while the LX is able to maintain the interaction with Met68 as in the solved structure, the LH counterpart early detaches from Cz binding pocket.References:[1] P. Jaishankar, E. Hansell, D. M. Zhao,P. S. Doyle, J. H. McKerrowb, A. R. Renslo, Bioorganic & Medicinal Chemistry Letters , 2008,18,624?628.[2] R. S. Ferreira,M. A. Dessoy, I.Pauli, M. L. Souza, R. Krogh, A.I. L. Sales, G. Oliva, L.C. Dias, A.D. Andricopulo, J. Med. Chem. 2014, 57, 2380−2392.[3] D. A. Case, T.E. Cheatham, T. Darden, H. Gohlke, R.Luo, K.M. Jr Merz, A. Onufriev, C. Simmerling, B. Wang, R.J. Woods,The Amber biomolecular simulation programs.J. Comput. Chem ,2005,26,1668-1688.[4] M. A. A. Ibrahim, J. Comput. Chem. 2011, 32, 2564-2574[5] R. W. Bader, Atoms in Molecules: A Quantum Theory, Oxford University Press, New York, 1990.Acknowledgements: We acknowledge SECyT-UNNE and CONICET for financial support. We acknowledge NVIDIA Corporation, the Geforce GTX Titan X GPU used for this research was donated by the NVIDIA Corporation.