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| Author(s): |
Leonardo Luiz Gomes Ferreira
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Carlos. |
| Institution: | Universidade de São Paulo (USP). Instituto de Física de São Carlos (IFSC/BT) |
| Defense date: | 2013-04-23 |
| Examining board members: |
Adriano Defini Andricopulo;
Hamilton Brandão Varela de Albuquerque;
Elizabeth Igne Ferreira;
Marco Edilson Freire de Lima;
Alessandro Silva Nascimento
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| Advisor: | Adriano Defini Andricopulo; Otavio Henrique Thiemann |
| Abstract | |
Neglected tropical diseases, which affect the poorest populations across the developing world, are a major global concern. The trypanosomiases are amongst the most serious neglected tropical diseases, and particularly, African trypanosomiasis (sleeping sickness), caused by the unicellular parasite Trypanosoma brucei, appears as a fatal condition. The glycolytic pathway emerges as a promising target among the metabolic pathways for the development of new drugs, due to its essential role in the ATP generating process in the bloodstream form of the parasite. The goal of this work is to identify new inhibitors for the glycolytic enzyme aldolase (EC 4.1.2.13) from Trypanosoma brucei. Inhibitors of this enzyme are drug candidates with high potential for clinical development, as the respective target enzyme was validated as a molecular target for the therapy of trypanosomiasis. The strategy employed in this study includes the integration of SBDD (structure-based drug design) and LBDD, (ligand-based drug design) for the identification of inhibitors of the target enzyme, through the combination of computational and experimental methodologies. Significant results were obtained, such as the identification of new small molecule inhibitors of the aldolase enzyme through high-throughput virtual screening. Additionally, it is highlighted the standardization of expression, purification and crystallization protocols for the target enzyme. As a component of the strategy for the identification of novel aldolase inhibitors, 2D and 3D QSAR models were developed, as well as molecular dynamics studies. (AU) | |
| FAPESP's process: | 08/10727-7 - Rational Design of New Inhibitors of the Enzymes Aldolase and Phosphofructokinase from Trypanosoma brucei |
| Grantee: | Leonardo Luiz Gomes Ferreira |
| Support Opportunities: | Scholarships in Brazil - Doctorate |