Molecular docking and molecular dynamics simulation studies of Trypanosoma cruzi triosephosphate isomerase inhibitors. Insights into the inhibition mechanism and selectivity

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. (C) 2015 Elsevier Inc. All rights reserved.