Metabolomic fingerprinting, molecular modelling and experimental bioprospection of Helianthus annuus seed cultivars as Pseudomonas aeruginosa LasR modulators.
Akshay Raghoonanadan, Yamkela Dweba, Christiana E Aruwa, Saheed Sabiu
{"title":"Metabolomic fingerprinting, molecular modelling and experimental bioprospection of Helianthus annuus seed cultivars as Pseudomonas aeruginosa LasR modulators.","authors":"Akshay Raghoonanadan, Yamkela Dweba, Christiana E Aruwa, Saheed Sabiu","doi":"10.1016/j.bioorg.2024.108046","DOIUrl":null,"url":null,"abstract":"<p><p>The Pseudomonas aeruginosa LasR quorum sensing system (QSS) is central to regulating the expression of several pathogenicity factors. Also, while seed- and/or plant-derived products have been investigated as QSS regulators, the impact of Helianthus annuus (Pannar sunflower seed cultivars) extracts and metabolites as LasR modulators remain underexplored. Thus, this study focused on the untargeted metabolomic profiling (Liquid Chromatography-Mass Spectrometry), in vitro and in silico (docking, pharmacokinetics, dynamic simulation) bioprospection of Pannar seed cultivars' extracts and metabolites as LasR modulators. The extracts showed significant QS modulating properties (motility, violacein, biofilm, cell attachment, pyocyanin inhibition) with the PAN 7102 CLP seed cultivar (74.3 %) being the most potent, compared to azithromycin (65 %) and cinnamaldehyde (62 %). Chemometric principal component analysis (PCA) analysis showed distinct metabolite signatures with 52.5 % variance across the six cultivars that was driven by aqueous and ethanolic extracts of PAN 7102, 7160, and 7156 cultivars. The presence of methoxymellein, hydroxytetradecanedioic acid, koninginin G, geoside, pinellic acid and methylpicraquassioside A were reported for the first time. The profiled metabolites were subjected to a 100-ns molecular dynamics simulation following molecular docking. Binding free energy (ΔG<sub>bind</sub>) calculations revealed obolactone (-48.26 kcal/mol), 1,4-bis(phenylglyoxaloyl)benzene (-45.06 kcal/mol), cyclocanaliculatin (-43.41 kcal/mol), 5-hydroxy-7-methoxy-2-phenylchroman-4-one (-39.18 kcal/mol) and lonchocarpin (-33.78 kcal/mol) as first-time putative leads relative to azithromycin (-32.09 kcal/mol). All lead metabolites also conformed to Lipinski's rule of 5 (Ro5), and their LasR bound complexes were thermodynamically stable and compact given their strong bond interactions. Findings indicate that metabolomic profiling remain key to identifying new compounds from underexplored species. H. annuus lead metabolites and extracts may also play key roles as LasR modulators. Further structural modification of the 5 leads could aid their development into novel, oral therapeutics targeting LasR to mitigate resistant P. aeruginosa infections.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"154 ","pages":"108046"},"PeriodicalIF":4.5000,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1016/j.bioorg.2024.108046","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The Pseudomonas aeruginosa LasR quorum sensing system (QSS) is central to regulating the expression of several pathogenicity factors. Also, while seed- and/or plant-derived products have been investigated as QSS regulators, the impact of Helianthus annuus (Pannar sunflower seed cultivars) extracts and metabolites as LasR modulators remain underexplored. Thus, this study focused on the untargeted metabolomic profiling (Liquid Chromatography-Mass Spectrometry), in vitro and in silico (docking, pharmacokinetics, dynamic simulation) bioprospection of Pannar seed cultivars' extracts and metabolites as LasR modulators. The extracts showed significant QS modulating properties (motility, violacein, biofilm, cell attachment, pyocyanin inhibition) with the PAN 7102 CLP seed cultivar (74.3 %) being the most potent, compared to azithromycin (65 %) and cinnamaldehyde (62 %). Chemometric principal component analysis (PCA) analysis showed distinct metabolite signatures with 52.5 % variance across the six cultivars that was driven by aqueous and ethanolic extracts of PAN 7102, 7160, and 7156 cultivars. The presence of methoxymellein, hydroxytetradecanedioic acid, koninginin G, geoside, pinellic acid and methylpicraquassioside A were reported for the first time. The profiled metabolites were subjected to a 100-ns molecular dynamics simulation following molecular docking. Binding free energy (ΔGbind) calculations revealed obolactone (-48.26 kcal/mol), 1,4-bis(phenylglyoxaloyl)benzene (-45.06 kcal/mol), cyclocanaliculatin (-43.41 kcal/mol), 5-hydroxy-7-methoxy-2-phenylchroman-4-one (-39.18 kcal/mol) and lonchocarpin (-33.78 kcal/mol) as first-time putative leads relative to azithromycin (-32.09 kcal/mol). All lead metabolites also conformed to Lipinski's rule of 5 (Ro5), and their LasR bound complexes were thermodynamically stable and compact given their strong bond interactions. Findings indicate that metabolomic profiling remain key to identifying new compounds from underexplored species. H. annuus lead metabolites and extracts may also play key roles as LasR modulators. Further structural modification of the 5 leads could aid their development into novel, oral therapeutics targeting LasR to mitigate resistant P. aeruginosa infections.
期刊介绍:
Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry.
For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature.
The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.