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Structure-based design of competitive and allosteric inhibitors of cruzain

Grant number: 18/03911-8
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): May 01, 2018
Effective date (End): May 31, 2021
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal Investigator:Fátima Pereira de Souza
Grantee:Lilian Hernández Alvarez
Home Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil
Associated scholarship(s):18/25311-2 - Pharmacological characterization and optimization of novel natural compounds with anti-Chagas activity, BE.EP.DR


Trypanosoma cruzi is the causative agent of Chagas Disease, a neglected infection affecting millions of people in tropical regions. There are several chemotherapeutic agents for the treatment of this disease, but most of them are inefficient and highly toxic. Cruzain is the major papain-like cysteine protease of T. cruzi. This enzyme is indispensable for the survival and propagation of the parasite and, therefore, is considered as a suitable drug target for control of Chagas Disease. Several experimental studies and computational predictions have been performed to characterize the cruzain binding site and specificity, facilitating the design of active-site directed drugs. The development of allosteric inhibitors constitutes a promising research field, since it may improve the accessibility to more selective and less toxic medicines. In this work, a strategy based on an integrated in silico and experimental approaches will be used for the discovery of both competitive and allosteric inhibitors of cruzain. A combination of Virtual Screening (VS), Molecular Dynamics (MD) simulations, binding free energy calculations and network-based modelling of residue interactions will be employed to select potential novel inhibitors and to characterize the molecular distinctive features of the apo form and the cruzain-inhibitor complexes. Finally, NMR experiments and enzymatic assays will be performed to characterize the interactions of cruzain-ligand systems. Those experiments will provide the insights into the allostery mechanism, and will allow the mapping of critical residues for protein-ligand interactions as well as the determination of equilibrium constants. (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)
HERNANDEZ GONZALEZ, JORGE ENRIQUE; ALVAREZ, LILIAN HERNANDEZ; PASCUTTI, PEDRO GERALDO; LEITE, VITOR B. P. Prediction of Noncompetitive Inhibitor Binding Mode Reveals Promising Site for Allosteric Modulation of Falcipain-2. Journal of Physical Chemistry B, v. 123, n. 34, SI, p. 7327-7342, AUG 29 2019. Web of Science Citations: 0.
ALVAREZ, LILIAN HERNANDEZ; BARRETO GOMES, DIEGO ENRY; HERNANDEZ GONZALEZ, JORGE ENRIQUE; PASCUTTI, PEDRO GERALDO. Dissecting a novel allosteric mechanism of cruzain: A computer-aided approach. PLoS One, v. 14, n. 1 JAN 25 2019. Web of Science Citations: 3.

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