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| Author(s): |
Emanuella Maria Barreto Fonseca
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Química |
| Defense date: | 2015-01-16 |
| Examining board members: |
Ricardo Aparicio;
Artur Torres Cordeiro;
Guilherme Menegon Arantes;
Fábio Cesar Gozzo;
Adalberto Bono Maurizio Sacchi Bassi
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| Advisor: | Ricardo Aparicio |
| Abstract | |
Cancer is a disease whose incidence and prevalence have reached alarming proportions, emerging today as a major public health problem. Protein phosphorylation is a dynamic and reversible event, governed by the opposite activities of protein tyrosine kinases and protein tyrosine phosphatases. High levels of the phosphatases LMW-PTP and CDC25B have been observed in a wide variety of tumors and, for this reason, they have been selected as targets for inhibitor development. Using in silico methods, a collection of approximately 500,000 fragments was assembled from a database of commercial compounds. For each enzyme, these fragments were subjected to different molecular docking protocols, through which 19 small molecules have been selected and purchased. The computational results were validated by enzyme inhibition assays, with the identification of new molecular scaffolds capable of inhibiting in more than 50% the enzyme activity, resulting in ligand efficiency values up to 0.33 kcal mol-1 per non-H atom. Similarly, a number of compounds derived from benzenophosphonic acid was tested against the LMW-PTP after docking studies, followed by crystallographic studies which resulted in two new structures: one of the apo protein and another of a complex LMW-PTP:inhibitor. In addition to the previously described active site, a second crystallographic site was identified, whose potential biological function, if confirmed, might open new possibilities to modulate LMW-PTP activity, in a perspective which demands further investigation. (AU) | |
| FAPESP's process: | 11/15792-4 - New inhibitors of LMW-PTP and CDC25B: fragment-based drug design using in silico methods, inhibition assays and Protein Crystallography |
| Grantee: | Emanuella Maria Barreto Fonseca |
| Support Opportunities: | Scholarships in Brazil - Doctorate |