title: Structural considerations for the rational design of selective anti-trypanosomal agents: the role of the aromatic clusters at the interface of triosephosphate isomerase dimer.
abstract: Seven benzothiazoles were successfully docked into the interface of both human and trypanosomal triosephosphate isomerases, and the binding free energies of each complex were calculated using the program AutoDock. Structural and energetical analysis of the complexes showed that large benzothiazoles could form more stable complexes with trypanosomal triosephosphate isomerase than with human triosephosphate isomerase. Thus, we hypothesize that the distribution of the residues forming the aromatic clusters at the enzyme's interface and the size of the inhibitors might play a crucial role in the selective inhibition of TcTIM. Following the findings here presented, it is possible to better determine the structural elements involved in the origin of the selectivity at the trypanosomal triosephosphate isomerase interface, and to enable efficient anti-trypanosomal drug design strategies.
authors.affiliation: Department of Physical Chemistry, FNS, Comenius University, Mlynská dolina, Bratislava 84215, Slovakia. fonck@correo.unam.mx
authors.forename: L Michel
authors.initials: LM
authors.lastname: Espinoza-Fonseca
authors.forename: José G
authors.initials: JG
authors.lastname: Trujillo-Ferrara
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D019281:Dimerization; D016503:Drug Delivery Systems / Q000379:methods; D015195:Drug Design; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry*; D014305:Triose-Phosphate Isomerase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D014344:Trypanocidal Agents / Q000737:chemistry*; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D013830:Thiadiazoles; D014344:Trypanocidal Agents; C015700:benzo-1,2,3-thiadiazole; D014305:Triose-Phosphate Isomerase