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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.

ABSTRACT: 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 IC₅₀ 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.

SUBMITTER: Marban-Gonzalez A

PROVIDER: S-EPMC8705689 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In the last few years, increasing numbers of viruses infecting fungi have been identified. In this study, we used an in silico approach for the analysis of deep RNA sequencing data in order to discover and characterize putative genomic ssRNA or dsRNA mycovirus sequences in Aspergillus fumigatus. RNA sequencing reads of A. fumigatus strains were mapped against the A. fumigatus Af293 reference genome. Unmapped reads were collected for de novo assembly. Contigs were analyzed by Blastx comparison with a mycovirus protein database. Assembled viral genomes were used as template for remapping of RNA sequencing reads. In total, deep RNA sequencing results from 11 A. fumigatus strains were analyzed for the presence of mycoviral genomic RNAs. In 9 out of 11 strains, putative mycoviral RNA genomes were identified. Three strains were infected with two different mycovirus species. Two strains were infected with Aspergillus fumigatus polymycovirus type-1 (AfuPmV-1). Four strains contained fully recovered genomic RNA of unknown narna-like viruses designated as Aspergillus fumigatus narnavirus-1 and Aspergillus fumigatus narnavirus-2 (AfuNV-1 and AfuNV-2). Both viruses showed 38% amino acid sequence identity to Beihai narna-like virus-21. Three strains contained partially recovered genomic RNA of an unknown narna-like virus. Two strains contained fully recovered genomic RNAs of an unknown partitivirus designated as Aspergillus fumigatus partitivirus-2 (AfuPV-2) which showed 50% amino acid sequence identity to Alternaria alternata partitivirus-1. Finally, one strain contained fully recovered genomic RNA of an unknown mitovirus designated as Aspergillus fumigatus mitovirus-1 (AfuMV-1) which showed 34% amino acid sequence identity to Sclerotina sclerotiorum mitovirus. In silico analysis of deep RNA sequencing results showed that a majority of the A. fumigatus strains used here were infected with mycoviruses. Four novel A. fumigatus RNA mycoviruses could be identified: two different Aspergillus fumigatus narna-like viruses, one Aspergillus fumigatus partitivirus, and one Aspergillus fumigatus mitovirus.

Dataset Information

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

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