title: The design and inhibitory profile of new benzimidazole derivatives against triosephosphate isomerase from Trypanosoma cruzi: a problem of residue motility.
abstract: To develop a new set of compounds with inhibitory activity against the triosephosphate isomerase of Trypanosoma cruzi (TcTIM), a group of benzimidazole derivatives was studied using four different docking procedures. These docking procedures differ in the number and type of mobile residues considered in the analysis. As a result of this methodology, a clustered analysis of plausible candidate structures was produced. A different set of previously synthesized compounds was used to validate this analysis. The validation showed that the best results correspond to the docking procedure in which the residues near the hydrophobic pocket of the protein's interface were considered mobile. A binding site for the best candidates was identified. Residues Tyr103, Glu105 and Lys113, among others, are important for the binding of this kind of compound. Residue Tyr103 is different in the human TIM, thus establishing a key feature for the future design of selective inhibitors.
authors.affiliation: Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, México DF 04510, Mexico.
authors.forename: Antonio
authors.initials: A
authors.lastname: Romo-Mancillas
authors.forename: Alfredo
authors.initials: A
authors.lastname: Téllez-Valencia
authors.forename: Lilián
authors.initials: L
authors.lastname: Yépez-Mulia
authors.forename: Francisco
authors.initials: F
authors.lastname: Hernández-Luis
authors.forename: Alicia
authors.initials: A
authors.lastname: Hernández-Campos
authors.forename: Rafael
authors.initials: R
authors.lastname: Castillo
mesh_terms: D020816:Amino Acid Motifs; D000981:Antiprotozoal Agents / Q000737:chemistry*; D001562:Benzimidazoles / Q000737:chemistry*; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D011485:Protein Binding; D015800:Protozoan Proteins / Q000737:chemistry*; D013499:Surface Properties; D014305:Triose-Phosphate Isomerase / Q000737:chemistry*; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D000981:Antiprotozoal Agents; D001562:Benzimidazoles; D015800:Protozoan Proteins; D014305:Triose-Phosphate Isomerase