Structural modelling and comparative analysis of homologous, analogous and specific proteins from Trypanosoma cruzi versus Homo sapiens: putative drug targets for chagas' disease treatment

Abstract

BackgroundTrypanosoma cruzi is the etiological agent of Chagas' disease, an endemic infection that causes thousands of deaths every year in Latin America. Therapeutic options remain inefficient, demanding the search for new drugs and/or new molecular targets. Such efforts can focus on proteins that are specific to the parasite, but analogous enzymes and enzymes with a three-dimensional (3D) structure sufficiently different from the corresponding host proteins may represent equally interesting targets. In order to find these targets we used the workflows MHOLline and AnEnΠ obtaining 3D models from homologous, analogous and specific proteins of Trypanosoma cruzi versus Homo sapiens.ResultsWe applied genome wide comparative modelling techniques to obtain 3D models for 3,286 predicted proteins of T. cruzi. In combination with comparative genome analysis to Homo sapiens, we were able to identify a subset of 397 enzyme sequences, of which 356 are homologous, 3 analogous and 38 specific to the parasite.ConclusionsIn this work, we present a set of 397 enzyme models of T. cruzi that can constitute potential structure-based drug targets to be investigated for the development of new strategies to fight Chagas' disease. The strategies presented here support the concept of structural analysis in conjunction with protein functional analysis as an interesting computational methodology to detect potential targets for structure-based rational drug design. For example, 2,4-dienoyl-CoA reductase (EC 1.3.1.34) and triacylglycerol lipase (EC 3.1.1.3), classified as analogous proteins in relation to H. sapiens enzymes, were identified as new potential molecular targets.

Structural Modeling and In Silico Analysis of Human Superoxide Dismutase 2

“…These sequences were submitted to the MHOLline workflow [10]. The theoretical models generated using MHOLline are presented in Figure 1.…”

“…The mutant (E66V, G76R, I82T and R156W) models were built using the MHOLline workflow [10] with the crystallographic structure of human SOD2 (PDB ID: 1LUV) as the template. I-Tasser was utilised for the ab initio modelling of the S10I and A16V mutants [13].…”

“…Structural theoretical models were created for the variants using comparative modelling performed in MHOLline [10]. MHOLline includes a set of programmes for protein structure analysis, including MODELLER [11] and PROCHECK [12].…”

Delivering on Promises? The Impact of Kinetoplastid Genomics on Sleeping Sickness, Chagas Disease and Leishmaniasis

“…23 In a similar study, Capriles and co-workers performed a comparative analysis with the T. cruzi genome and the human genome and used comparative modelling techniques to predict 3D protein structures. 24 They were able to identify 397 T.…”

“…24 Trypanosomatid parasites lack de novo biosynthesis of purines and depend entirely on the salvage pathway to meet their purine requirements. 25 Because enzymes and transporters of the purine salvage pathway show sufficient differences between trypanosomatids and humans, it is considered as a potential drug target against these parasites.…”