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Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from Aspergillus fumigatus: In Silico Drug Design Studies

Chitinases represent an alternative therapeutic target for opportunistic invasive mycosis since they are necessary for fungal cell wall remodeling. This study presents the design of new chitinase inhibitors from a known hydrolysis intermediate. Firstly, a bioinformatic analysis of Aspergillus fumiga...

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Autores principales: Marbán-González, Alberto, Hernández-Mendoza, Armando, Ordóñez, Mario, Razo-Hernández, Rodrigo Said, Viveros-Ceballos, José Luis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8705689/
https://www.ncbi.nlm.nih.gov/pubmed/34946697
http://dx.doi.org/10.3390/molecules26247606
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author Marbán-González, Alberto
Hernández-Mendoza, Armando
Ordóñez, Mario
Razo-Hernández, Rodrigo Said
Viveros-Ceballos, José Luis
author_facet Marbán-González, Alberto
Hernández-Mendoza, Armando
Ordóñez, Mario
Razo-Hernández, Rodrigo Said
Viveros-Ceballos, José Luis
author_sort Marbán-González, Alberto
collection PubMed
description Chitinases represent an alternative therapeutic target for opportunistic invasive mycosis since they are necessary for fungal cell wall remodeling. This study presents the design of new chitinase inhibitors from a known hydrolysis intermediate. Firstly, a bioinformatic analysis of Aspergillus fumigatus chitinase B1 (AfChiB1) and chitotriosidase (CHIT1) by length and conservation was done to obtain consensus sequences, and molecular homology models of fungi and human chitinases were built to determine their structural differences. We explored the octahydroisoindolone scaffold as a potential new antifungal series by means of its structural and electronic features. Therefore, we evaluated several synthesis-safe octahydroisoindolone derivatives by molecular docking and evaluated their AfChiB1 interaction profile. Additionally, compounds with the best interaction profile (1–5) were docked within the CHIT1 catalytic site to evaluate their selectivity over AfChiB1. Furthermore, we considered the interaction energy (MolDock score) and a lipophilic parameter (aLogP) for the selection of the best candidates. Based on these descriptors, we constructed a mathematical model for the IC(50) prediction of our candidates (60–200 μM), using experimental known inhibitors of AfChiB1. As a final step, ADME characteristics were obtained for all the candidates, showing that 5 is our best designed hit, which possesses the best pharmacodynamic and pharmacokinetic character.
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spelling pubmed-87056892021-12-25 Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from Aspergillus fumigatus: In Silico Drug Design Studies Marbán-González, Alberto Hernández-Mendoza, Armando Ordóñez, Mario Razo-Hernández, Rodrigo Said Viveros-Ceballos, José Luis Molecules Article Chitinases represent an alternative therapeutic target for opportunistic invasive mycosis since they are necessary for fungal cell wall remodeling. This study presents the design of new chitinase inhibitors from a known hydrolysis intermediate. Firstly, a bioinformatic analysis of Aspergillus fumigatus chitinase B1 (AfChiB1) and chitotriosidase (CHIT1) by length and conservation was done to obtain consensus sequences, and molecular homology models of fungi and human chitinases were built to determine their structural differences. We explored the octahydroisoindolone scaffold as a potential new antifungal series by means of its structural and electronic features. Therefore, we evaluated several synthesis-safe octahydroisoindolone derivatives by molecular docking and evaluated their AfChiB1 interaction profile. Additionally, compounds with the best interaction profile (1–5) were docked within the CHIT1 catalytic site to evaluate their selectivity over AfChiB1. Furthermore, we considered the interaction energy (MolDock score) and a lipophilic parameter (aLogP) for the selection of the best candidates. Based on these descriptors, we constructed a mathematical model for the IC(50) prediction of our candidates (60–200 μM), using experimental known inhibitors of AfChiB1. As a final step, ADME characteristics were obtained for all the candidates, showing that 5 is our best designed hit, which possesses the best pharmacodynamic and pharmacokinetic character. MDPI 2021-12-15 /pmc/articles/PMC8705689/ /pubmed/34946697 http://dx.doi.org/10.3390/molecules26247606 Text en © 2021 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
Marbán-González, Alberto
Hernández-Mendoza, Armando
Ordóñez, Mario
Razo-Hernández, Rodrigo Said
Viveros-Ceballos, José Luis
Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from Aspergillus fumigatus: In Silico Drug Design Studies
title Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from Aspergillus fumigatus: In Silico Drug Design Studies
title_full Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from Aspergillus fumigatus: In Silico Drug Design Studies
title_fullStr Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from Aspergillus fumigatus: In Silico Drug Design Studies
title_full_unstemmed Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from Aspergillus fumigatus: In Silico Drug Design Studies
title_short Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from Aspergillus fumigatus: In Silico Drug Design Studies
title_sort discovery of octahydroisoindolone as a scaffold for the selective inhibition of chitinase b1 from aspergillus fumigatus: in silico drug design studies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8705689/
https://www.ncbi.nlm.nih.gov/pubmed/34946697
http://dx.doi.org/10.3390/molecules26247606
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