title: Molecular docking and molecular dynamics simulation studies of Trypanosoma cruzi triosephosphate isomerase inhibitors. Insights into the inhibition mechanism and selectivity.
abstract: Trypanosoma cruzi (T. cruzi) triosephosphate isomerase (TcTIM) is a glycolytic enzyme essential for parasite survival and has been considered an interesting target for the development of new antichagasic compounds. The homodimeric enzyme is catalytically active only as a dimer. Interestingly, significant differences exist between the human and parasite TIMs interfaces with a sequence identity of 52%. Therefore, compounds able to specifically disrupt TcTIM but not Homo sapiens TIM (hTIM) dimer interface could become selective antichagasic drugs. In the present work, the binding modes of 1,2,4-thiadiazol, phenazine and 1,2,6-thiadiazine derivatives to TcTIM were investigated using molecular docking combined with molecular dynamics (MD) simulations. The results show that phenazine and 1,2,6-thiadiazine derivatives, 2 and 3, act as dimer-disrupting inhibitors of TcTIM having also allosteric effects in the conformation of the active site. On the other hand, the 1,2,4-thiadiazol derivative 1 binds into the active site causing a significant decrease in enzyme mobility in both monomers. The loss of conformational flexibility upon compound 1 binding suggests that this inhibitor could be preventing essential motions of the enzyme required for optimal activity. The lack of inhibitory activity of 1 against hTIM was also investigated and seems to be related with the high mobility of hTIM which would hinder the formation of a stable ligand-enzyme complex. This work has contributed to understand the mechanism of action of this kind of inhibitors and could result of great help for future rational novel drug design.
authors.affiliation: Laboratorio de Química Teórica y Computacional, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay; Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Lucía
authors.initials: L
authors.lastname: Minini
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Guzmán
authors.initials: G
authors.lastname: Álvarez
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay; Área de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.affiliation: Laboratorio de Química Teórica y Computacional, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay. Electronic address: amerlino@fcien.edu.uy.
authors.forename: Alicia
authors.initials: A
authors.lastname: Merlino
mesh_terms: D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010619:Phenazines / Q000737:chemistry / Q000378:metabolism; D013829:Thiadiazines / Q000737:chemistry / Q000378:metabolism; D013830:Thiadiazoles / Q000737:chemistry / Q000378:metabolism; D014305:Triose-Phosphate Isomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D010619:Phenazines; D013829:Thiadiazines; D013830:Thiadiazoles; C000598831:phenazine; D014305:Triose-Phosphate Isomerase
keywords: Dimer-disrupting inhibitors; Molecular docking; Molecular dynamics; Rational drug design; Selective TcTIM inhibitors