Molecular docking and molecular dynamics simulation studies of Trypanosoma cruzi triosephosphate isomerase inhibitors. Insights into the inhibition mechanism and selectivity |
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Affiliation: | 1. Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India;2. College of Pharmacy & Health Science, Ajman University, United Arab Emirates;3. Department of Food Science and Nutrition, Faculty of Food and Agricultural Sciences, King Saud University, 2460, Riyadh 11451, Saudi Arabia;4. Department of Biochemistry, College of Sciences, King Saud University, Riyadh, Saudi Arabia |
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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. |
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Keywords: | Molecular docking Molecular dynamics Dimer-disrupting inhibitors Rational drug design |
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