Halogen bonding. A suitable interaction for structural optimization of lead compounds with trypanocidal activity

LUCRECIA BOGADO; ADRIANO LUCHI; DARÍO J. R. DUARTE; EMILIO L. ANGELINA; NÉLIDA M. PERUCHENA

Santiago de Chile

Congreso; XLIV International Congress of Theoretical Chemists of Latin Expression; 2018

Available chemotherapy for Chagas disease (CD) treatment presents severe side effects and drug-resistance has been observed in some trypanosome strains. Therefore the discovery of new, safer and more effective drugs to treat CD is necessary. Cruzain (Cz) belongs to the family of papain-like cysteine proteases and plays a vital role in each stage of the parasite life cycle. Accordingly, it is presented as a possible pharmacological target for treatment of this disease. The starting point for this study was the knowledge of Cz structure bound non-covalently to brominated ligand B95 (N- [2- (1H-benzimidazol-2-yl) ethyl] -2- (2-bromophenoxy)) acetamide) where bromine atom from the bromobenzene moiety forms an halogen bond (EX) with sulfur atom from residue Met68. Interestingly, this brominated ligand has an activity 14 times greater than its non-halogenated counterpart [1]. The importance of this EX for the stabilization of the biomolecular complex was studied by Molecular Dynamic (MD) simulations and the topological analysis of the Laplacian of electronic density, L(r). The Cz-B95 complex was obtained from the Protein Data Bank (PDB:3KKU) and MD simulations were performed using the AMBER program package [2]. 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. EP parametrization was carried out following the procedure of Ibrahim [3]. MD trajectories show that B95 remains anchored at the Cz binding pocket during the simulations but the non-halogenated analog of B95 early detaches from it. Results demonstrate that an unusual Br∙∙∙S contact with Met68 sulfur atom is essential for the stabilization of the Cz-B95 complex. The topological analysis of L(r) reveals that this particular interaction can be considered to be triple Lewis acid-base interactions. Finally, the properties of this interaction makes it useful for lead optimization of anti-chagasic compounds directed towards Cz.Acknowledgments: The authors acknowledge SEGCyT-UNNE and CONICET for financial support and NVIDIA Corporation for the donation of Geforce GTX Titan X GPU.References:[1] R. Ferreira, M. Dessoy, I.Pauli, M. Souza, R. Krogh, A. Sales, G. Oliva, L. Dias, A. Andricopulo, J. Med. Chem. 57, (2014), 2380.[2] D. Case, T. Cheatham, T. Darden, H. Gohlke, R.Luo, K. Jr Merz, A. Onufriev, C. Simmerling, B. Wang, R. Woods, J. Comput. Chem ,26, (2005), 1668.[3] M. Ibrahim, J. Comput. Chem. 32, (2011), 2564.