Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from <i>Aspergillus fumigatus</i>: 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 <i>Aspergill...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/24/7606 |
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| author | Alberto Marbán-González Armando Hernández-Mendoza Mario Ordóñez Rodrigo Said Razo-Hernández José Luis Viveros-Ceballos |
| author_facet | Alberto Marbán-González Armando Hernández-Mendoza Mario Ordóñez Rodrigo Said Razo-Hernández José Luis Viveros-Ceballos |
| author_sort | Alberto Marbán-González |
| collection | DOAJ |
| 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 <i>Aspergillus fumigatus</i> 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 (<b>1</b>–<b>5</b>) 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<sub>50</sub> 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 <b>5</b> is our best designed hit, which possesses the best pharmacodynamic and pharmacokinetic character. |
| first_indexed | 2024-03-10T03:28:48Z |
| format | Article |
| id | doaj.art-e8d1f8f67772479c8d3e8a4d86243dd5 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T03:28:48Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-e8d1f8f67772479c8d3e8a4d86243dd52023-11-23T09:46:46ZengMDPI AGMolecules1420-30492021-12-012624760610.3390/molecules26247606Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from <i>Aspergillus fumigatus</i>: In Silico Drug Design StudiesAlberto Marbán-González0Armando Hernández-Mendoza1Mario Ordóñez2Rodrigo Said Razo-Hernández3José Luis Viveros-Ceballos4Centro de Investigaciones Químicas, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Cuernavaca 62209, MexicoCentro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Cuernavaca 62209, MexicoCentro de Investigaciones Químicas, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Cuernavaca 62209, MexicoCentro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Cuernavaca 62209, MexicoCentro de Investigaciones Químicas, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Cuernavaca 62209, MexicoChitinases 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 <i>Aspergillus fumigatus</i> 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 (<b>1</b>–<b>5</b>) 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<sub>50</sub> 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 <b>5</b> is our best designed hit, which possesses the best pharmacodynamic and pharmacokinetic character.https://www.mdpi.com/1420-3049/26/24/7606bioinformatic analysischitinase AfChiB1molecular dockingmolecular similarityoxazolinium ion |
| spellingShingle | Alberto Marbán-González Armando Hernández-Mendoza Mario Ordóñez Rodrigo Said Razo-Hernández José Luis Viveros-Ceballos Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from <i>Aspergillus fumigatus</i>: In Silico Drug Design Studies Molecules bioinformatic analysis chitinase AfChiB1 molecular docking molecular similarity oxazolinium ion |
| title | Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from <i>Aspergillus fumigatus</i>: In Silico Drug Design Studies |
| title_full | Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from <i>Aspergillus fumigatus</i>: In Silico Drug Design Studies |
| title_fullStr | Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from <i>Aspergillus fumigatus</i>: In Silico Drug Design Studies |
| title_full_unstemmed | Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from <i>Aspergillus fumigatus</i>: In Silico Drug Design Studies |
| title_short | Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from <i>Aspergillus fumigatus</i>: In Silico Drug Design Studies |
| title_sort | discovery of octahydroisoindolone as a scaffold for the selective inhibition of chitinase b1 from i aspergillus fumigatus i in silico drug design studies |
| topic | bioinformatic analysis chitinase AfChiB1 molecular docking molecular similarity oxazolinium ion |
| url | https://www.mdpi.com/1420-3049/26/24/7606 |
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