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Antibacterial and Antitumor Drug Design: Applying Advanced Computational Methods for the Identification of New Inhibitor Classes Against Bacterial and Human Topoisomerase Enzyme

Grant number: 12/00360-4
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): August 01, 2012
Effective date (End): July 31, 2015
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Reinaldo Marchetto
Grantee:Aderson Zottis
Host Institution: Instituto de Química (IQ). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil


Topoisomerases play a crucial role in DNA replication for both bacterial and human cells, which make them good targets for designing and developing new antibacterial and antitumor drugs. The aim of this project is to design and develop new more potent and selective non-peptide and peptide inhibitors of bacterial and human topoisomerases. Also, metabolic stability is an additional property that will be considered for improving efficiency by cyclization procedure for in the case of peptide compounds. Initital steps involve application of advanced computational methods of molecular modeling, based on both 3D structures of the macromolecular targets and focused sets of known inhibitors. A virtual screening campaign of chemical libraries will be performed to identify and select promising new scaffolds with high structural diversity. Peptide compounds will be synthesized and small molecules from other chemical classes purchased from chemical companies. Then enzymatic assays are carried out using spectrophotometric and fluorimetric techniques to validate the hits and establish the mechanism of their inhibition. After, isothermal calorimetry experiments will be applied for selecting the compounds exhibiting particular thermodynamic features that allow hit-to-lead process for further mass spectrometry assays. The point here is to shed light on the kinetic mechanism as well as the thermodynamic interaction of topoisomerases-inhibitor complexes though supporting succeeding steps in this research. Structure-activity relationships studies will provide new dataset for designing novel inhibitors to be synthesized or commercially acquired for building models through QSAR studies. The rate of true binders from hits identified in computational studies will also contribute to evaluate the robustness of the softwares and hence select important physicochemical parameters to be considered for in silico studies of a specific enzyme target. This feedback assures more efficiency to this process of searching and selecting bioactive molecules against topoisomerases.

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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)
PASSALACQUA, THAIS G.; TORRES, FABIO A. E.; NOGUEIRA, CAMILA T.; DE ALMEIDA, LETICIA; DEL CISTIA, MAYARA L.; DOS SANTOS, MARIANA B.; REGASINI, LUIS O.; GRAMINHA, MARCIA A. S.; MARCHETTO, REINALDO; ZOTTIS, ADERSON. The 2 `,4 `-dihydroxychalcone could be explored to develop new inhibitors against the glycerol-3-phosphate dehydrogenase from Leishmania species. Bioorganic & Medicinal Chemistry Letters, v. 25, n. 17, p. 3564-3568, . (12/00360-4)
CAMILA A. ROCHA; PAULO R. S. SANCHES; REINALDO MARCHETTO; ADERSON ZOTTIS. The Octahydroindene Carboxyl Substructure from Dihydrobetulinic Acid is Essential to Inhibit Topoisomerase IB from Leishmania donovani. Journal of the Brazilian Chemical Society, v. 27, n. 3, p. 591-598, . (12/00360-4)

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