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Medicinal Chemistry strategies (LBDD and SBDD) in the search of tripanomatides sirtuin 2 inhibitors


Neglected diseases are caused by infectious and parasitic agents such as viruses, bacteria, protozoa and helminths. These diseases are prevalent in low-income populations living in developing countries and are responsible for incapacitating and bringing millions to death. They are neglected because of the great medical relevance, accompanied by a few attention of the governments and pharmaceutical industries. Among these diseases we highlight trypanosomatids as Chagas disease (T. cruzi), sleeping sickness (T. brucei) and Leishmaniosis (Leishmania sp.). The chemotherapy against these diseases are oldest, present several side effects, and drug resistance has been observed. In case of Chagas disease there are only two drugs both not effective in chronic phase of the disease. This panorama suggests the urgent need in the discovery of new chemotherapy agents to promote better life condition to infected people. In general, trypanosomatids have a complex cell cycle and respond to various environmental conditions as the organism of different hosts and vectors. Sirtuins were shown to be essential for the in vitro growth of these parasites in different evolutive forms. In the case of parasites such as trypanosomatids in general, overexpression of Sir2 is related to the survival of amastigotes. Sir2 inhibitors like sirtinol showed efficacy as leishmanicidal and antichagasic in vivo assays. Thus, these evidences indicate that the Sir2 of trypanosomatids can be considered as biological targets in the search and development of new drugs. Despite the major objective of the Project is applying modern medicinal chemistry tools in search of the new chemical entities inhibitors of the parasite Sir2. In the search of the Sir2 inhibitors will be applied Structure and Ligand based drug design. For this the integration of the computational (Comparative Model, Molecular Fields interactions, pharmacophore models and virtual screening) with experimental methods (organic synthesis, protein expression and biological assays) will be performed in the identification of the potent and selective parasite Sir2 inhibitors drug candidates. (AU)

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Scientific publications (7)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FERRAZ, WITOR RIBEIRO; GOMES, RENAN AUGUSTO; NOVAES, ANDRE LUIS; GOULART TROSSINI, GUSTAVO HENRIQUE. Ligand and structure-based virtual screening applied to the SARS-CoV-2 main protease: anin silicorepurposing study. Future Medicinal Chemistry, v. 12, n. 20, . (17/25543-8)
KRONENBERGER, THALES; FERREIRA, GLAUCIO MONTEIRO; FERREIRA DE SOUZA, ALFREDO DANILO; SANTOS, SORAYA DA SILVA; POSO, ANTTI; RIBEIRO, JOAO AUGUSTO; TAVARES, MAURICIO TEMOTHEO; PAVAN, FERNANDO ROGERIO; GOULART TROSSINI, GUSTAVO HENRIQUE; BERTACINE DIAS, MARCIO VINICIUS; et al. Design, synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors. Bioorganic & Medicinal Chemistry, v. 28, n. 15, . (13/18160-4, 17/00689-0, 13/15906-5, 17/25543-8)
VASCONCELOS, STANLEY N. S.; MEISSNER, KAMILA A.; FERRAZ, WITOR R.; TROSSINI, GUSTAVO H. G.; WRENGER, CARSTEN; STEFANI, HELIO A.. Indole-3-glyoxyl tyrosine: synthesis and antimalarial activity against Plasmodium falciparum. Future Medicinal Chemistry, v. 11, n. 6, p. 525-538, . (15/26722-8, 12/12807-3, 13/17960-7, 17/25543-8, 16/24790-9, 12/00424-2)
KIMANI, NJOGU M.; MATASYOH, JOSPHAT C.; KAISER, MARCEL; NOGUEIRA, MAURO S.; TROSSINI, GUSTAVO H. G.; SCHMIDT, THOMAS J.. Complementary Quantitative Structure-Activity Relationship Models for the Antitrypanosomal Activity of Sesquiterpene Lactones. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 19, n. 12, . (17/25543-8)
ALMEIDA, VITOR MEDEIROS; CHAUDHURI, APALA; CARDOSO, MARCUS VINICIUS CANGUSSU; MATSUYAMA, BRUNO YASUI; FERREIRA, GLAUCIO MONTEIRO; GOULART TROSSINI, GUSTAVO HENRIQUE; SALINAS, ROBERTO KOPKE; LORIA, J. PATRICK; MARANA, SANDRO ROBERTO. Role of a high centrality residue in protein dynamics and thermal stability. Journal of Structural Biology, v. 213, n. 3, . (19/24112-9, 17/25543-8, 18/25952-8, 16/12899-6)
GOMES, RENAN AUGUSTO; FORNARI, EVELIN; SILVA ROCHA, ANA CAROLINA; TRIPODI, GUSTAVO LUIS; DA SILVA EMERY, FLAVIO; GOULART TROSSINI, GUSTAVO HENRIQUE. Parasitic sirtuin 2 as an opportunity in drug discovery. Future Medicinal Chemistry, v. 13, n. 16, p. 1397-1409, . (17/06568-0, 13/15650-0, 17/25543-8)
MOURA GATTI, FERNANDO DE; GOMES, RENAN AUGUSTO; DA FONSECA, AMANDA LUISA; CARDOSO LIMA, ELYS JULIANE; VITAL-FUJII, DRIELLI GOMES; TARANTO, ALEX GUTERRES; PILLA VAROTTI, FERNANDO DE; GOULART TROSSINI, GUSTAVO HENRIQUE. Antiplasmodial activity of sulfonylhydrazones: in vitro and in silico approaches. Future Medicinal Chemistry, v. 13, n. 3, p. 233-250, . (13/15650-0, 17/25543-8)

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