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Identification of novel drug targets for Helicobacter pylori: structure-based virtual screening of potential inhibitors against DAH7PS protein involved in the shikimate pathway

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Názov: Identification of novel drug targets for Helicobacter pylori: structure-based virtual screening of potential inhibitors against DAH7PS protein involved in the shikimate pathway
Autori: Narjes Noori Goodarzi, Mahshid Khazani Asforooshani, Behzad Shahbazi, Nayereh Rezaie Rahimi, Farzad Badmasti
Zdroj: Front Bioinform
Frontiers in Bioinformatics, Vol 4 (2024)
Informácie o vydavateľovi: Frontiers Media SA, 2024.
Rok vydania: 2024
Predmety: Helicobacter pylori, structure-based virtual screening, shikimate pathway, Bioinformatics, Computer applications to medicine. Medical informatics, R858-859.7, StreptomeDB, DAH7PS
Popis: BackgroundHelicobacter pylori, a bacterium associated with severe gastrointestinal diseases and malignancies, poses a significant challenge because of its increasing antibiotic resistance rates. This study aimed to identify potential drug targets and inhibitors against H. pylori using a structure-based virtual screening (SBVS) approach.MethodsCore-proteome analysis of 132 H. pylori genomes was performed using the EDGAR database. Essential genes were identified and human and gut microbiota homolog proteins were excluded. The DAH7PS protein involved in the shikimate pathway was selected for the structure-based virtual screening (SBVS) approach. The tertiary structure of the protein was predicted through homology modeling (based on PDB ID: 5UXM). Molecular docking was performed to identify potential inhibitors of DAH7PS among StreptomeDB compounds using the AutoDock Vina tool. Molecular dynamics (MD) simulations assessed the stability of DAH7PS-ligand complexes. The complexes were further evaluated in terms of their binding affinity, Lipinski’s Rule of Five, and ADMET properties.ResultsA total of 54 novel drug targets with desirable properties were identified. DAH7PS was selected for further investigation, and virtual screening of StreptomeDB compounds yielded 36 high-affinity binding of the ligands. Two small molecules, 6,8-Dihydroxyisocoumarin-3-carboxylic acid and Epicatechin, also showed favorable RO5 and ADMET properties. MD simulations confirmed the stability and reliability of DAH7PS-ligand complexes, indicating their potential as inhibitors.ConclusionThis study identified 54 novel drug targets against H. pylori. The DAH7PS protein as a promising drug target was evaluated using a computer-aided drug design. 6,8-Dihydroxyisocoumarin-3-carboxylic acid and Epicatechin demonstrated desirable properties and stable interactions, highlighting their potential to inhibit DAH7PS as an essential protein. Undoubtedly, more experimental validations are needed to advance these findings into practical therapies for treating drug-resistant H. pylori.
Druh dokumentu: Article
Other literature type
ISSN: 2673-7647
DOI: 10.3389/fbinf.2024.1482338
Prístupová URL adresa: https://pubmed.ncbi.nlm.nih.gov/39493576
https://doaj.org/article/485cc91e1e1b476686af08db79532c5b
Rights: CC BY
Prístupové číslo: edsair.doi.dedup.....57e181b4a07b0bda4d22855a3a16bf72
Databáza: OpenAIRE
Popis
Abstrakt:BackgroundHelicobacter pylori, a bacterium associated with severe gastrointestinal diseases and malignancies, poses a significant challenge because of its increasing antibiotic resistance rates. This study aimed to identify potential drug targets and inhibitors against H. pylori using a structure-based virtual screening (SBVS) approach.MethodsCore-proteome analysis of 132 H. pylori genomes was performed using the EDGAR database. Essential genes were identified and human and gut microbiota homolog proteins were excluded. The DAH7PS protein involved in the shikimate pathway was selected for the structure-based virtual screening (SBVS) approach. The tertiary structure of the protein was predicted through homology modeling (based on PDB ID: 5UXM). Molecular docking was performed to identify potential inhibitors of DAH7PS among StreptomeDB compounds using the AutoDock Vina tool. Molecular dynamics (MD) simulations assessed the stability of DAH7PS-ligand complexes. The complexes were further evaluated in terms of their binding affinity, Lipinski’s Rule of Five, and ADMET properties.ResultsA total of 54 novel drug targets with desirable properties were identified. DAH7PS was selected for further investigation, and virtual screening of StreptomeDB compounds yielded 36 high-affinity binding of the ligands. Two small molecules, 6,8-Dihydroxyisocoumarin-3-carboxylic acid and Epicatechin, also showed favorable RO5 and ADMET properties. MD simulations confirmed the stability and reliability of DAH7PS-ligand complexes, indicating their potential as inhibitors.ConclusionThis study identified 54 novel drug targets against H. pylori. The DAH7PS protein as a promising drug target was evaluated using a computer-aided drug design. 6,8-Dihydroxyisocoumarin-3-carboxylic acid and Epicatechin demonstrated desirable properties and stable interactions, highlighting their potential to inhibit DAH7PS as an essential protein. Undoubtedly, more experimental validations are needed to advance these findings into practical therapies for treating drug-resistant H. pylori.
ISSN:26737647
DOI:10.3389/fbinf.2024.1482338