In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2

Detalhes bibliográficos
Autor(a) principal: Hernández González, Jorge Enrique [UNESP]
Data de Publicação: 2021
Outros Autores: Salas-Sarduy, Emir, Hernández Alvarez, Lilian [UNESP], Barreto Gomes, Diego Enry, Pascutti, Pedro Geraldo, Oostenbrink, Chris, Leite, Vitor B. P. [UNESP]
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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spelling 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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