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Molecular design of trypanocidal agents for the treatment of Chagas Disease

Grant number: 11/20572-3
Support type:Research Grants - Visiting Researcher Grant - International
Duration: May 01, 2012 - April 30, 2013
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Carlos Alberto Montanari
Grantee:Carlos Alberto Montanari
Visiting researcher: Peter W. Kenny
Visiting researcher institution: Pessoa Física - Inglaterra, England
Home Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil

Abstract

The Medicinal Chemistry Group of the IQSC / USP has been devoting time to the design of enzyme inhibitors within the overall concept of the drug discovery and development endeavor. The first step of the process is to identify chemicals that are classified as ligands of enzyme targets consisting of proteins from Trypanosoma cruzi derived and expressed in recombinant forms. The three enzymes used as target by the group are glyceraldehyde 3-phosphate dehydrogenase (TcGAPDH), dihydroorotate dehydrogenase (TcDHODH) and cruzain. Of these three targets, our group has sought to contribute to the recognition that they are good targets for the search for trypanosomatid agents. This is extremely important because the goal of finding new agents acting via known mode of actions continues to be of outstanding importance in the discovery pipeline. Moreover, it is important to stress that the identification is performed in the early stages of the drug design pipeline that upsurge to the optimization stage as in the present proposal. The inhibitors identified in earlier studies carried out in our group from primary assays were confirmed in secondary assays when studies of structure-activity relationships (SAR) were carried out. Hence, assuming that the active sites of the enzymes have maximum affinity for substances that are drug-like, the identification of inhibitors that act by competitive mechanism to the active site appears as likely to be valuable for target and T. cruzi inhibition validations. Considering that such inhibitors identified in previous work act on the active sites and bearing in mind that some of them are also active against infective forms of T. cruzi, therefore validating our hypothesis we can conclude that this is a good approach for the pursuit of new trypanosomatid agents acting against the study enzymes. The major objective of this proposal is the use of drug repositioning strategies to identify cruzain inhibitors with enhanced T. cruzi activity. (AU)

Scientific publications
(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)
KENNY, PETER W.; LEITAO, ANDREI; MONTANARI, CARLOS A. Ligand efficiency metrics considered harmful. Journal of Computer-Aided Molecular Design, v. 28, n. 7, p. 699-710, JUL 2014. Web of Science Citations: 28.
KENNY, PETER W.; MONTANARI, CARLOS A.; PROKOPCZYK, IGOR M.; SALA, FERNANDA A.; SARTORI, GERALDO RODRIGUES. Automated molecule editing in molecular design. Journal of Computer-Aided Molecular Design, v. 27, n. 8, p. 655-664, AUG 2013. Web of Science Citations: 6.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.