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Quantum Biochemistry Screening and In Vitro Evaluation of Leishmania Metalloproteinase Inhibitors

Leishmanolysin, also known as major promastigote protease (PSP) or gp63, is the most abundant surface glycoprotein of Leishmania spp., and has been extensively studied and recognized as the main parasite virulence factor. Characterized as a metalloprotease, gp63 can be powerfully inactivated in the...

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Autores principales: Moreno, Cláudia Jassica Gonçalves, Farias, Henriqueta Monalisa, de Lima Medeiros, Rafael, de Brito Pinto, Talita Katiane, de Freitas Oliveira, Johny Wysllas, de Sousa, Francimar Lopes, de Medeiros, Mayara Jane Campos, Amorim-Carmo, Bruno, Santos-Gomes, Gabriela, de Lima Pontes, Daniel, Rocha, Hugo Alexandre Oliveira, Frazão, Nilton Fereira, Silva, Marcelo Sousa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9368959/
https://www.ncbi.nlm.nih.gov/pubmed/35955687
http://dx.doi.org/10.3390/ijms23158553
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author Moreno, Cláudia Jassica Gonçalves
Farias, Henriqueta Monalisa
de Lima Medeiros, Rafael
de Brito Pinto, Talita Katiane
de Freitas Oliveira, Johny Wysllas
de Sousa, Francimar Lopes
de Medeiros, Mayara Jane Campos
Amorim-Carmo, Bruno
Santos-Gomes, Gabriela
de Lima Pontes, Daniel
Rocha, Hugo Alexandre Oliveira
Frazão, Nilton Fereira
Silva, Marcelo Sousa
author_facet Moreno, Cláudia Jassica Gonçalves
Farias, Henriqueta Monalisa
de Lima Medeiros, Rafael
de Brito Pinto, Talita Katiane
de Freitas Oliveira, Johny Wysllas
de Sousa, Francimar Lopes
de Medeiros, Mayara Jane Campos
Amorim-Carmo, Bruno
Santos-Gomes, Gabriela
de Lima Pontes, Daniel
Rocha, Hugo Alexandre Oliveira
Frazão, Nilton Fereira
Silva, Marcelo Sousa
author_sort Moreno, Cláudia Jassica Gonçalves
collection PubMed
description Leishmanolysin, also known as major promastigote protease (PSP) or gp63, is the most abundant surface glycoprotein of Leishmania spp., and has been extensively studied and recognized as the main parasite virulence factor. Characterized as a metalloprotease, gp63 can be powerfully inactivated in the presence of a metal chelator. In this study, we first used the structural parameters of a 7-hydroxycoumarin derivative, L1 compound, to evaluate the theoretical–computational experiments against gp63, comparing it with an available metal chelator already described. The methodology followed was (i) analysis of the three-dimensional structure of gp63 as well as its active site, and searching the literature and molecular databases for possible inhibitors; (ii) molecular docking simulations and investigation of the interactions in the generated protein–ligand complexes; and (iii) the individual energy of the gp63 amino acids that interacted most with the ligands of interest was quantified by ab initio calculations using Molecular Fraction with Conjugated Caps (MFCC). MFCC still allowed the final quantum balance calculations of the protein interaction to be obtained with each inhibitor candidate binder. L1 obtained the best energy quantum balance result with −2 eV, followed by DETC (−1.4 eV), doxycycline (−1.3 eV), and 4-terpineol (−0.6 eV), and showed evidence of covalent binding in the enzyme active site. In vitro experiments confirmed L1 as highly effective against L. amazonensis parasites. The compound also exhibited a low cytotoxicity profile against mammalian RAW and 3T3 cells lines, presenting a selective index of 149.19 and 380.64 µM, respectively. L1 induced promastigote forms’ death by necrosis and the ultrastructural analysis revealed disruption in membrane integrity. Furthermore, leakage of the contents and destruction of the parasite were confirmed by Spectroscopy Dispersion analysis. These results together suggested L1 has a potential effect against L. amazonensis, the etiologic agent of diffuse leishmaniasis, and the only one that currently does not have a satisfactory treatment.
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spelling pubmed-93689592022-08-12 Quantum Biochemistry Screening and In Vitro Evaluation of Leishmania Metalloproteinase Inhibitors Moreno, Cláudia Jassica Gonçalves Farias, Henriqueta Monalisa de Lima Medeiros, Rafael de Brito Pinto, Talita Katiane de Freitas Oliveira, Johny Wysllas de Sousa, Francimar Lopes de Medeiros, Mayara Jane Campos Amorim-Carmo, Bruno Santos-Gomes, Gabriela de Lima Pontes, Daniel Rocha, Hugo Alexandre Oliveira Frazão, Nilton Fereira Silva, Marcelo Sousa Int J Mol Sci Article Leishmanolysin, also known as major promastigote protease (PSP) or gp63, is the most abundant surface glycoprotein of Leishmania spp., and has been extensively studied and recognized as the main parasite virulence factor. Characterized as a metalloprotease, gp63 can be powerfully inactivated in the presence of a metal chelator. In this study, we first used the structural parameters of a 7-hydroxycoumarin derivative, L1 compound, to evaluate the theoretical–computational experiments against gp63, comparing it with an available metal chelator already described. The methodology followed was (i) analysis of the three-dimensional structure of gp63 as well as its active site, and searching the literature and molecular databases for possible inhibitors; (ii) molecular docking simulations and investigation of the interactions in the generated protein–ligand complexes; and (iii) the individual energy of the gp63 amino acids that interacted most with the ligands of interest was quantified by ab initio calculations using Molecular Fraction with Conjugated Caps (MFCC). MFCC still allowed the final quantum balance calculations of the protein interaction to be obtained with each inhibitor candidate binder. L1 obtained the best energy quantum balance result with −2 eV, followed by DETC (−1.4 eV), doxycycline (−1.3 eV), and 4-terpineol (−0.6 eV), and showed evidence of covalent binding in the enzyme active site. In vitro experiments confirmed L1 as highly effective against L. amazonensis parasites. The compound also exhibited a low cytotoxicity profile against mammalian RAW and 3T3 cells lines, presenting a selective index of 149.19 and 380.64 µM, respectively. L1 induced promastigote forms’ death by necrosis and the ultrastructural analysis revealed disruption in membrane integrity. Furthermore, leakage of the contents and destruction of the parasite were confirmed by Spectroscopy Dispersion analysis. These results together suggested L1 has a potential effect against L. amazonensis, the etiologic agent of diffuse leishmaniasis, and the only one that currently does not have a satisfactory treatment. MDPI 2022-08-02 /pmc/articles/PMC9368959/ /pubmed/35955687 http://dx.doi.org/10.3390/ijms23158553 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Moreno, Cláudia Jassica Gonçalves
Farias, Henriqueta Monalisa
de Lima Medeiros, Rafael
de Brito Pinto, Talita Katiane
de Freitas Oliveira, Johny Wysllas
de Sousa, Francimar Lopes
de Medeiros, Mayara Jane Campos
Amorim-Carmo, Bruno
Santos-Gomes, Gabriela
de Lima Pontes, Daniel
Rocha, Hugo Alexandre Oliveira
Frazão, Nilton Fereira
Silva, Marcelo Sousa
Quantum Biochemistry Screening and In Vitro Evaluation of Leishmania Metalloproteinase Inhibitors
title Quantum Biochemistry Screening and In Vitro Evaluation of Leishmania Metalloproteinase Inhibitors
title_full Quantum Biochemistry Screening and In Vitro Evaluation of Leishmania Metalloproteinase Inhibitors
title_fullStr Quantum Biochemistry Screening and In Vitro Evaluation of Leishmania Metalloproteinase Inhibitors
title_full_unstemmed Quantum Biochemistry Screening and In Vitro Evaluation of Leishmania Metalloproteinase Inhibitors
title_short Quantum Biochemistry Screening and In Vitro Evaluation of Leishmania Metalloproteinase Inhibitors
title_sort quantum biochemistry screening and in vitro evaluation of leishmania metalloproteinase inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9368959/
https://www.ncbi.nlm.nih.gov/pubmed/35955687
http://dx.doi.org/10.3390/ijms23158553
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