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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Dissecting a novel allosteric mechanism of cruzain: A computer-aided approach

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Alvarez, Lilian Hernandez [1] ; Barreto Gomes, Diego Enry [2, 3] ; Hernandez Gonzalez, Jorge Enrique [1] ; Pascutti, Pedro Geraldo [4]
Total Authors: 4
[1] Univ Estadual Paulista, Dept Fis, Inst Biociencias Letras & Ciencias Exatas, Sao Jose Do Rio Preto, SP - Brazil
[2] Inst Nacl Metrol Qual & Tecnol INMETRO, Diretoria Metrol Aplicada Ciencias Vida DIMAV, Rio De Janeiro - Brazil
[3] Univ Strasbourg, Inst Chim, Strasbourg - France
[4] Univ Fed Rio De Janeiro UFRJ, Inst Biofis Carlos Chagas Filho, Rio De Janeiro - Brazil
Total Affiliations: 4
Document type: Journal article
Source: PLoS One; v. 14, n. 1 JAN 25 2019.
Web of Science Citations: 3

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 highly toxic and generate resistance. Currently, the development of allosteric inhibitors constitutes a promising research field, since it can improve the accessibility to more selective and less toxic medicines. To date, the allosteric drugs prediction is a state-of-the-art topic in rational structure-based computational design. In this work, a simulation strategy was developed for computational discovery of allosteric inhibitors, and it was applied to cruzain, a promising target and the major cysteine protease of T. cruzi. Molecular dynamics simulations, binding free energy calculations and network-based modelling of residue interactions were combined to characterize and compare molecular distinctive features of the apo form and the cruzain-allosteric inhibitor complexes. By using geometry-based criteria on trajectory snapshots, we predicted two main allosteric sites suitable for drug targeting. The results suggest dissimilar mechanisms exerted by the same allosteric site when binding different potential allosteric inhibitors. Finally, we identified the residues involved in suboptimal paths linking the identified site and the orthosteric site. The present study constitutes the first approximation to the design of cruzain allosteric inhibitors and may serve for future pharmacological intervention. Here, no major effects on active site structure were observed due to compound binding (modification of distance and angles between catalytic residues), which indicates that allosteric regulation in cruzain might be mediated via alterations of its dynamical properties similarly to allosteric inhibition of human cathepsin K (HCatK). The current findings are particularly relevant for the design of allosteric modulators of papain-like cysteine proteases. (AU)

FAPESP's process: 18/03911-8 - Structure-based design of competitive and allosteric inhibitors of cruzain
Grantee:Lilian Hernández Alvarez
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 16/24587-9 - In silico identification of novel competitive and alosteric inhibitors of falcipains 2 and 3
Grantee:Jorge Enrique Hernández González
Support type: Scholarships in Brazil - Doctorate