Evento
Halogen Bond Interactions for Design of Trypanosome Cruzi Inhibitors
Bogado, María Lucrecia
; Luchi, Adriano Martín
; Gómez Chávez, José Leonardo
; Duarte, Darío Jorge Roberto
; Sosa, Gladis Laura; Angelina, Emilio Luis
; Peruchena, Nelida Maria
Tipo del evento:
Reunión
Nombre del evento:
4th Scientific Meeting of the Research Network Natural Products against Neglected Diseases
Fecha del evento:
04/12/2018
Institución Organizadora:
Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco;
Título del Libro:
Book of abstracts: 4th Scientific Meeting of the Research Network Natural Products against Neglected Diseases
Editorial:
Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica
ISBN:
978-987-47034-0-8
Idioma:
Inglés
Clasificación temática:
Resumen
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.
Palabras clave:
NEGLECTED DISEASES
,
CRUZIPAINE
,
MOLECULAR DYNAMIC
,
QTAIM
Archivos asociados
Licencia
Identificadores
Colecciones
Eventos(CCT - NORDESTE)
Eventos de CTRO.CIENTIFICO TECNOL.CONICET - NORDESTE
Eventos de CTRO.CIENTIFICO TECNOL.CONICET - NORDESTE
Eventos(IQUIBA-NEA)
Eventos de INSTITUTO DE QUIMICA BASICA Y APLICADA DEL NORDESTE ARGENTINO
Eventos de INSTITUTO DE QUIMICA BASICA Y APLICADA DEL NORDESTE ARGENTINO
Citación
Halogen Bond Interactions for Design of Trypanosome Cruzi Inhibitors; 4th Scientific Meeting of the Research Network Natural Products against Neglected Diseases; Buenos Aires; Argentina; 2018; 188-189
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