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Optimized hidden target screening for very polar molecules in surface waters including a compound database inquiry.

ABSTRACT: Highly polar trace organic compounds, which are persistent, mobile, and toxic (PMT) or are very persistent and very mobile (vPvM) in the aquatic environment, may pose a risk to surface water, ground water, and drinking water supplies. Despite the advances in liquid chromatography-mass spectrometry, there often exists an analytical blind spot when it comes to very polar chemicals. This study seeks to make a broad polarity range analytically accessible by means of serially coupling reversed-phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC) to high-resolution mass spectrometry (HRMS). Moreover, a workflow is presented using optimized data processing of nontarget screening (NTS) data and subsequently generating candidate lists for the identification of very polar molecules via an open-access NTS platform and implemented compound database. First, key input parameters and filters of the so-called feature extraction algorithms were identified, and numerical performance indicators were defined to systematically optimize the data processing method. Second, all features from the very polar HILIC elution window were uploaded to the STOFF-IDENT database as part of the FOR-IDENT open-access NTS platform, which contains additional physicochemical information, and the features matched with potential compounds by their accurate mass. The hit list was filtered for compounds with a negative log D value, indicating that they were (very) polar. For instance, 46 features were assigned to 64 candidate compounds originating from a set of 33 samples from the Isar river in Germany. Three PMT candidates (e.g., guanylurea, melamine, and 1,3-dimethylimidazolidin-2-one) were illustratively validated using the respective reference standards. In conclusion, these findings demonstrate that polarity-extended chromatography reproducibly retards and separates (very) polar compounds from surface waters. These findings further indicate that a transparent and robust data processing workflow for nontarget screening data is available for addressing new (very) polar substances in the aqueous environment.

SUBMITTER: Minkus S

PROVIDER: S-EPMC8206052 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Diseases caused by new viruses costs thousands if not millions of human lives and trillions of dollars in damage to the global economy. Despite the rapid development of vaccines for SARS-CoV-2, the lack of small molecule antiviral drugs that work against multiple viral families (broad-spectrum antivirals; BSAs) has left the entire worldâ€™s human population vulnerable to the infection between the beginning of the outbreak and the widespread availability of vaccines. Developing BSAs is an attractive, yet challenging, approach that could prevent the next, inevitable, viral outbreak from becoming a global catastrophe. To explore whether historical medicinal chemistry efforts suggest the possibility of discovering novel BSAs, we (i) identified, collected, curated, and integrated all chemical bioactivity data available in ChEMBL for molecules tested in respective assays for 13 emerging viruses that, based on published literature, hold the greatest potential threat to global human health; (ii) identified and solved the challenges related to data annotation accuracy including assay description ambiguity, missing cell or target information, and incorrect BioAssay Ontology (BAO) annotations; (iii) developed a highly curated and thoroughly annotated database of compounds tested in both phenotypic (21,392 entries) and target-based (11,123 entries) assays for these viruses; and (iv) identified a subset of compounds showing BSA activity. For the latter task, we eliminated inconclusive and annotated duplicative entries by checking the concordance between multiple assay results and identified eight compounds active against 3-4 viruses from the phenotypic data, 16 compounds active against two viruses from the target-based data, and 35 compounds active in at least one phenotypic and one target-based assay. The pilot version of our SMACC (Small Molecule Antiviral Compound Collection) database contains over 32,500 entries for 13 viruses. Our analysis indicates that previous research yielded very small number of BSA compounds. We posit that focused and coordinated efforts strategically targeting the discovery of such agents must be established and maintained going forward. The SMACC database publicly available at https://smacc.mml.unc.edu may serve as a reference for virologists and medicinal chemists working on the development of novel BSA agents in preparation for future viral outbreaks.

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Optimized hidden target screening for very polar molecules in surface waters including a compound database inquiry.

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