Molecular networking as a dereplication strategy for monitoring metabolites of natural product treated cancer cells

Abstract

Rationale Natural products have been great sources for drug discovery. However, the structures of natural products are diverse and difficult to elucidate. Cordyceps militaris is a parasitic fungus which usually grows on host insects. The metabolites of C. militaris have been reported to act as chemotherapeutic agents. In this study, we aimed for the structural elucidation of specialized metabolites derived from C. militaris, and the metabolic impact in leukemia cells. Methods We describe a liquid chromatography data‐dependent mass spectrometric platform combining tandem mass analysis and molecular networking. Leukemia cells treated with C. militaris extract and control groups were visualized in terms of their metabolic profiles using Global Natural Product Social (GNPS) molecular networking. By this method, we were able to elucidate the structures of metabolites from medicinal fungus extracts and cancer cells and then to recognize their changes in a semi‐quantitative manner. Results Using C. militaris and leukemia cells as examples, we found that approximately 100 new ion species were present in the treated leukemia cells, suggesting a highly altered metabolic profile. Specifically, based on the tandem mass spectral similarity, we proposed that cordycepin, a key fungus‐derived therapeutic agent known for its antitumor activity, was transformed into its methylthio form in leukemia cells. Conclusions The platform described provides an ability to investigate complex molecular interactions of natural products in mammalian cells. By incorporating tandem mass spectrometry and molecular networking, we were able to reveal the chemical modification of crude bioactive compounds, for example potential bioactive compounds which might be modified from cordycepin. We envision that such a mass spectrometry (MS)‐based workflow, combined with other metabolomics platforms, would enable much wider applicability to cell biology and be of great potential to pharmacological study as well as drug discovery.

Polyene Macrolactams from Marine and Terrestrial Sources: Structure, Production Strategies, Biosynthesis and Bioactivities

“…Remarkably, many studies used the genomic prescience of natural products to choose the prioritization of feature response data for further isolation. A wide variety of statistical and analytical techniques based on algorithms of machine learning combined with visualized response map was applied to improve prioritization, such as global natural products social molecular networking (GNPS) and MS-based visualizing techniques [85][86][87]. With the assistance of genomic analysis [88] and predicting potential drug candidates from organisms and monitoring metabolites and mapping analysis of metabolomics via liquid chromatography-mass spectrometry (LC-MS)/MS [53,72], the known metabolites were identified and excluded.…”

In situnet fishing of α-glucosidase inhibitors from evening primrose (Oenothera biennis) defatted seeds by combination of LC-MS/MS, molecular networking, affinity-based ultrafiltration, and molecular docking

“…18 Global Natural Products Social Molecular Networking (GNPS, ) is the largest natural product database that allows researchers to collect and deposit extensive MS/MS data on natural product standards to enable rapid identification of known compounds by searching and matching the tandem mass spectral database. 19,20 Consequently, the combination of LC-MS/MS, GNPS-based molecular networking, and affinity-based ultrafiltration may provide an excellent tool for in situ net fishing bioactive compounds in natural product extracts. Therefore, in this study, to assess the potential of DSEP as functional food ingredients and identify α-glucosidase inhibitors in DSEP, an in situ net fishing strategy was proposed by combination of LC-MS/MS, GNPS-based molecular networking, affinity-based ultrafiltration, and molecular docking.…”

Optimization of LC-MS2 Data Acquisition Parameters for Molecular Networking Applied to Marine Natural Products

“…Molecular networking is now broadly used in the field of natural products (NP) with the introduction of online molecular networking Global Natural Products Social (GNPS) platform, developed by Wang et al [ 3 ] in 2016. GNPS has been applied to a wide range of applications including dereplication [ 4 , 5 , 6 , 7 ], metabolomics [ 8 , 9 , 10 , 11 ], and genome mining [ 12 , 13 ].…”