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

Registro completo de metadados
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.creatorAlvarez, Lilian Hernandez-
Autor(es): dc.creatorBarreto Gomes, Diego Enry-
Autor(es): dc.creatorHernandez Gonzalez, Jorge Enrique-
Autor(es): dc.creatorPascutti, Pedro Geraldo-
Data de aceite: dc.date.accessioned2021-03-11T01:15:07Z-
Data de disponibilização: dc.date.available2021-03-11T01:15:07Z-
Data de envio: dc.date.issued2019-10-04-
Data de envio: dc.date.issued2019-10-04-
Data de envio: dc.date.issued2019-01-25-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1371/journal.pone.0211227-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/185366-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/185366-
Descrição: dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)-
Descrição: dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)-
Descrição: dc.descriptionProcesso FAPESP: 2018/03911-8-
Descrição: dc.descriptionProcesso FAPESP: 2016/24587-9-
Descrição: dc.descriptionCAPES: 031/2013 PRO-DEFESA 3-
Descrição: dc.descriptionCAPES: 613-
Descrição: dc.descriptionTrypanosoma 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.-
Formato: dc.format41-
Idioma: dc.languageen-
Publicador: dc.publisherPublic Library Science-
Relação: dc.relationPlos One-
Direitos: dc.rightsopenAccess-
Título: dc.titleDissecting a novel allosteric mechanism of cruzain: A computer-aided approach-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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