Tetracycline Derivatives Inhibit Plasmodial Cysteine Protease Falcipain-2 through Binding to a Distal Allosteric Site
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1021/acs.jcim.1c01189 http://hdl.handle.net/11449/230172 |
Resumo: | Allosteric inhibitors regulate enzyme activity from remote and usually specific pockets. As they promise an avenue for less toxic and safer drugs, the identification and characterization of allosteric inhibitors has gained great academic and biomedical interest in recent years. Research on falcipain-2 (FP-2), the major papain-like cysteine hemoglobinase of Plasmodium falciparum, might benefit from this strategy to overcome the low selectivity against human cathepsins shown by active site-directed inhibitors. Encouraged by our previous finding that methacycline inhibits FP-2 noncompetitively, here we assessed other five tetracycline derivatives against this target and characterized their inhibition mechanism. As previously shown for methacycline, tetracycline derivatives inhibited FP-2 in a noncompetitive fashion, with Ki values ranging from 121 to 190 μM. A possible binding to the S′ side of the FP-2 active site, similar to that described by X-ray crystallography (PDB: 6SSZ) for the noncompetitive inhibitor E-chalcone 48 (EC48), was experimentally discarded by kinetic analysis using a large peptidyl substrate spanning the whole active site. By combining lengthy molecular dynamics (MD) simulations that allowed methacycline to diffuse from solution to different FP-2 surface regions and free energy calculations, we predicted the most likely binding mode of the ligand. Of note, the proposed binding pose explains the low differences in Ki values observed for the tested tetracycline derivatives and the calculated binding free energies match the experimental values. Overall, this study has implications for the design of novel allosteric inhibitors against FP-2 and sets the basis for further optimization of the tetracycline scaffold to produce more potent and selective inhibitors. |
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Tetracycline Derivatives Inhibit Plasmodial Cysteine Protease Falcipain-2 through Binding to a Distal Allosteric SiteAllosteric inhibitors regulate enzyme activity from remote and usually specific pockets. As they promise an avenue for less toxic and safer drugs, the identification and characterization of allosteric inhibitors has gained great academic and biomedical interest in recent years. Research on falcipain-2 (FP-2), the major papain-like cysteine hemoglobinase of Plasmodium falciparum, might benefit from this strategy to overcome the low selectivity against human cathepsins shown by active site-directed inhibitors. Encouraged by our previous finding that methacycline inhibits FP-2 noncompetitively, here we assessed other five tetracycline derivatives against this target and characterized their inhibition mechanism. As previously shown for methacycline, tetracycline derivatives inhibited FP-2 in a noncompetitive fashion, with Ki values ranging from 121 to 190 μM. A possible binding to the S′ side of the FP-2 active site, similar to that described by X-ray crystallography (PDB: 6SSZ) for the noncompetitive inhibitor E-chalcone 48 (EC48), was experimentally discarded by kinetic analysis using a large peptidyl substrate spanning the whole active site. By combining lengthy molecular dynamics (MD) simulations that allowed methacycline to diffuse from solution to different FP-2 surface regions and free energy calculations, we predicted the most likely binding mode of the ligand. Of note, the proposed binding pose explains the low differences in Ki values observed for the tested tetracycline derivatives and the calculated binding free energies match the experimental values. Overall, this study has implications for the design of novel allosteric inhibitors against FP-2 and sets the basis for further optimization of the tetracycline scaffold to produce more potent and selective inhibitors.Departamento de Física Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista Júlio de Mesquita Filho, Rua Cristóvão Colombo, 2265, Jardim Nazareth, São José do Rio PretoLaboratory of Bioactive Compounds Research and Development (LIDeB) Department of Biological Sciences Exact Sciences College Universidad Nacional de la PlataChemistry and Physics Department Center for Genetic Engineering and BiotechnologyInst. de Invest. Biotecnologicas Dr. Rodolfo Ugalde-Universidad Nacional de San Martin-CONICET, San MartínDepartamento de Física Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista Júlio de Mesquita Filho, Rua Cristóvão Colombo, 2265, Jardim Nazareth, São José do Rio PretoUniversidade Estadual Paulista (UNESP)Universidad Nacional de la PlataCenter for Genetic Engineering and BiotechnologyInst. de Invest. Biotecnologicas Dr. Rodolfo Ugalde-Universidad Nacional de San Martin-CONICETHernández González, Jorge Enrique [UNESP]Alberca, Lucas N.Masforrol González, YordankaReyes Acosta, OsvaldoTalevi, AlanSalas-Sarduy, Emir2022-04-29T08:38:15Z2022-04-29T08:38:15Z2022-01-10info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article159-175http://dx.doi.org/10.1021/acs.jcim.1c01189Journal of Chemical Information and Modeling, v. 62, n. 1, p. 159-175, 2022.1520-51421549-9596http://hdl.handle.net/11449/23017210.1021/acs.jcim.1c011892-s2.0-85122320076Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengJournal of Chemical Information and Modelinginfo:eu-repo/semantics/openAccess2022-04-29T08:38:15Zoai:repositorio.unesp.br:11449/230172Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T14:12:13.862866Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Tetracycline Derivatives Inhibit Plasmodial Cysteine Protease Falcipain-2 through Binding to a Distal Allosteric Site |
title |
Tetracycline Derivatives Inhibit Plasmodial Cysteine Protease Falcipain-2 through Binding to a Distal Allosteric Site |
spellingShingle |
Tetracycline Derivatives Inhibit Plasmodial Cysteine Protease Falcipain-2 through Binding to a Distal Allosteric Site Hernández González, Jorge Enrique [UNESP] |
title_short |
Tetracycline Derivatives Inhibit Plasmodial Cysteine Protease Falcipain-2 through Binding to a Distal Allosteric Site |
title_full |
Tetracycline Derivatives Inhibit Plasmodial Cysteine Protease Falcipain-2 through Binding to a Distal Allosteric Site |
title_fullStr |
Tetracycline Derivatives Inhibit Plasmodial Cysteine Protease Falcipain-2 through Binding to a Distal Allosteric Site |
title_full_unstemmed |
Tetracycline Derivatives Inhibit Plasmodial Cysteine Protease Falcipain-2 through Binding to a Distal Allosteric Site |
title_sort |
Tetracycline Derivatives Inhibit Plasmodial Cysteine Protease Falcipain-2 through Binding to a Distal Allosteric Site |
author |
Hernández González, Jorge Enrique [UNESP] |
author_facet |
Hernández González, Jorge Enrique [UNESP] Alberca, Lucas N. Masforrol González, Yordanka Reyes Acosta, Osvaldo Talevi, Alan Salas-Sarduy, Emir |
author_role |
author |
author2 |
Alberca, Lucas N. Masforrol González, Yordanka Reyes Acosta, Osvaldo Talevi, Alan Salas-Sarduy, Emir |
author2_role |
author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (UNESP) Universidad Nacional de la Plata Center for Genetic Engineering and Biotechnology Inst. de Invest. Biotecnologicas Dr. Rodolfo Ugalde-Universidad Nacional de San Martin-CONICET |
dc.contributor.author.fl_str_mv |
Hernández González, Jorge Enrique [UNESP] Alberca, Lucas N. Masforrol González, Yordanka Reyes Acosta, Osvaldo Talevi, Alan Salas-Sarduy, Emir |
description |
Allosteric inhibitors regulate enzyme activity from remote and usually specific pockets. As they promise an avenue for less toxic and safer drugs, the identification and characterization of allosteric inhibitors has gained great academic and biomedical interest in recent years. Research on falcipain-2 (FP-2), the major papain-like cysteine hemoglobinase of Plasmodium falciparum, might benefit from this strategy to overcome the low selectivity against human cathepsins shown by active site-directed inhibitors. Encouraged by our previous finding that methacycline inhibits FP-2 noncompetitively, here we assessed other five tetracycline derivatives against this target and characterized their inhibition mechanism. As previously shown for methacycline, tetracycline derivatives inhibited FP-2 in a noncompetitive fashion, with Ki values ranging from 121 to 190 μM. A possible binding to the S′ side of the FP-2 active site, similar to that described by X-ray crystallography (PDB: 6SSZ) for the noncompetitive inhibitor E-chalcone 48 (EC48), was experimentally discarded by kinetic analysis using a large peptidyl substrate spanning the whole active site. By combining lengthy molecular dynamics (MD) simulations that allowed methacycline to diffuse from solution to different FP-2 surface regions and free energy calculations, we predicted the most likely binding mode of the ligand. Of note, the proposed binding pose explains the low differences in Ki values observed for the tested tetracycline derivatives and the calculated binding free energies match the experimental values. Overall, this study has implications for the design of novel allosteric inhibitors against FP-2 and sets the basis for further optimization of the tetracycline scaffold to produce more potent and selective inhibitors. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-04-29T08:38:15Z 2022-04-29T08:38:15Z 2022-01-10 |
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/10.1021/acs.jcim.1c01189 Journal of Chemical Information and Modeling, v. 62, n. 1, p. 159-175, 2022. 1520-5142 1549-9596 http://hdl.handle.net/11449/230172 10.1021/acs.jcim.1c01189 2-s2.0-85122320076 |
url |
http://dx.doi.org/10.1021/acs.jcim.1c01189 http://hdl.handle.net/11449/230172 |
identifier_str_mv |
Journal of Chemical Information and Modeling, v. 62, n. 1, p. 159-175, 2022. 1520-5142 1549-9596 10.1021/acs.jcim.1c01189 2-s2.0-85122320076 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Journal of Chemical Information and Modeling |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
159-175 |
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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1808128331969724416 |