In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1007/s10822-021-00420-7 http://hdl.handle.net/11449/229665 |
Resumo: | Falcipain-2 (FP-2) is a Plasmodium falciparum hemoglobinase widely targeted in the search for antimalarials. FP-2 can be allosterically modulated by various noncompetitive inhibitors that have been serendipitously identified. Moreover, the crystal structures of two inhibitors bound to an allosteric site, termed site 6, of the homolog enzyme human cathepsin K (hCatK) suggest that the equivalent region in FP-2 might play a similar role. Here, we conduct the rational identification of FP-2 inhibitors through virtual screenings (VS) of compounds into several pocket-like conformations of site 6, sampled during molecular dynamics (MD) simulations of the free enzyme. Two noncompetitive inhibitors, ZINC03225317 and ZINC72290660, were confirmed using in vitro enzymatic assays and their poses into site 6 led to calculated binding free energies matching the experimental ones. Our results provide strong evidence about the allosteric inhibition of FP-2 through binding of small molecules to site 6, thus opening the way toward the discovery of new inhibitors against this enzyme. |
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In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2AllosteryFalcipain-2Molecular dynamicsNoncompetitive inhibitorVirtual screeningFalcipain-2 (FP-2) is a Plasmodium falciparum hemoglobinase widely targeted in the search for antimalarials. FP-2 can be allosterically modulated by various noncompetitive inhibitors that have been serendipitously identified. Moreover, the crystal structures of two inhibitors bound to an allosteric site, termed site 6, of the homolog enzyme human cathepsin K (hCatK) suggest that the equivalent region in FP-2 might play a similar role. Here, we conduct the rational identification of FP-2 inhibitors through virtual screenings (VS) of compounds into several pocket-like conformations of site 6, sampled during molecular dynamics (MD) simulations of the free enzyme. Two noncompetitive inhibitors, ZINC03225317 and ZINC72290660, were confirmed using in vitro enzymatic assays and their poses into site 6 led to calculated binding free energies matching the experimental ones. Our results provide strong evidence about the allosteric inhibition of FP-2 through binding of small molecules to site 6, thus opening the way toward the discovery of new inhibitors against this enzyme.Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)Departamento de Física Instituto de Biociências Letras e Ciências Exatas – Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Rua Cristóvão Colombo 2265, Jardim NazarethLaboratório de Modelagem e Dinâmica Molecular Instituto de Biofı́sica Carlos Chagas Filho Universidade Federal do Rio de Janeiro, Ave. Carlos Chagas Filho – Universidade Federal do Rio de Janeiro (UFRJ), Ave. Carlos Chagas Filho, 373, CCS-Bloco D sala 30, Cidade Universitária Ilha de FundãoInstitute for Molecular Modeling and Simulation Department for Material Sciences and Process Engineering – University of Natural Resources and Life Sciences (BOKU) Vienna, Muthgasse 18Instituto de Investigaciones Biotecnológicas Dr. Rodolfo Ugalde Universidad Nacional de San Martín CONICET, San MartínInstituto de Ciências Exatas Universidade Federal de Juiz de Fora (UFJF), Rua José Lourenço Kelmer, s/n – Campus Universitário, Bairro São PedroDepartamento de Física Instituto de Biociências Letras e Ciências Exatas – Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Rua Cristóvão Colombo 2265, Jardim NazarethUniversidade Estadual Paulista (UNESP)Universidade Federal do Rio de Janeiro (UFRJ)ViennaCONICETUniversidade Federal de Juiz de Fora (UFJF)Hernández González, Jorge Enrique [UNESP]Salas-Sarduy, EmirHernández Alvarez, Lilian [UNESP]Barreto Gomes, Diego EnryPascutti, Pedro GeraldoOostenbrink, ChrisLeite, Vitor B. P. [UNESP]2022-04-29T08:35:01Z2022-04-29T08:35:01Z2021-01-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1007/s10822-021-00420-7Journal of Computer-Aided Molecular Design.1573-49510920-654Xhttp://hdl.handle.net/11449/22966510.1007/s10822-021-00420-72-s2.0-85116578557Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengJournal of Computer-Aided Molecular Designinfo:eu-repo/semantics/openAccess2022-04-29T08:35:01Zoai:repositorio.unesp.br:11449/229665Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T18:47:52.722534Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2 |
title |
In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2 |
spellingShingle |
In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2 Hernández González, Jorge Enrique [UNESP] Allostery Falcipain-2 Molecular dynamics Noncompetitive inhibitor Virtual screening |
title_short |
In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2 |
title_full |
In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2 |
title_fullStr |
In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2 |
title_full_unstemmed |
In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2 |
title_sort |
In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2 |
author |
Hernández González, Jorge Enrique [UNESP] |
author_facet |
Hernández González, Jorge Enrique [UNESP] Salas-Sarduy, Emir Hernández Alvarez, Lilian [UNESP] Barreto Gomes, Diego Enry Pascutti, Pedro Geraldo Oostenbrink, Chris Leite, Vitor B. P. [UNESP] |
author_role |
author |
author2 |
Salas-Sarduy, Emir Hernández Alvarez, Lilian [UNESP] Barreto Gomes, Diego Enry Pascutti, Pedro Geraldo Oostenbrink, Chris Leite, Vitor B. P. [UNESP] |
author2_role |
author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (UNESP) Universidade Federal do Rio de Janeiro (UFRJ) Vienna CONICET Universidade Federal de Juiz de Fora (UFJF) |
dc.contributor.author.fl_str_mv |
Hernández González, Jorge Enrique [UNESP] Salas-Sarduy, Emir Hernández Alvarez, Lilian [UNESP] Barreto Gomes, Diego Enry Pascutti, Pedro Geraldo Oostenbrink, Chris Leite, Vitor B. P. [UNESP] |
dc.subject.por.fl_str_mv |
Allostery Falcipain-2 Molecular dynamics Noncompetitive inhibitor Virtual screening |
topic |
Allostery Falcipain-2 Molecular dynamics Noncompetitive inhibitor Virtual screening |
description |
Falcipain-2 (FP-2) is a Plasmodium falciparum hemoglobinase widely targeted in the search for antimalarials. FP-2 can be allosterically modulated by various noncompetitive inhibitors that have been serendipitously identified. Moreover, the crystal structures of two inhibitors bound to an allosteric site, termed site 6, of the homolog enzyme human cathepsin K (hCatK) suggest that the equivalent region in FP-2 might play a similar role. Here, we conduct the rational identification of FP-2 inhibitors through virtual screenings (VS) of compounds into several pocket-like conformations of site 6, sampled during molecular dynamics (MD) simulations of the free enzyme. Two noncompetitive inhibitors, ZINC03225317 and ZINC72290660, were confirmed using in vitro enzymatic assays and their poses into site 6 led to calculated binding free energies matching the experimental ones. Our results provide strong evidence about the allosteric inhibition of FP-2 through binding of small molecules to site 6, thus opening the way toward the discovery of new inhibitors against this enzyme. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-01-01 2022-04-29T08:35:01Z 2022-04-29T08:35:01Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1007/s10822-021-00420-7 Journal of Computer-Aided Molecular Design. 1573-4951 0920-654X http://hdl.handle.net/11449/229665 10.1007/s10822-021-00420-7 2-s2.0-85116578557 |
url |
http://dx.doi.org/10.1007/s10822-021-00420-7 http://hdl.handle.net/11449/229665 |
identifier_str_mv |
Journal of Computer-Aided Molecular Design. 1573-4951 0920-654X 10.1007/s10822-021-00420-7 2-s2.0-85116578557 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Journal of Computer-Aided Molecular Design |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
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1808128980572700672 |