Polypharmacology-labeled molecular networking: An analytical technology workflow for accelerated identification of multiple bioactive constituents in complex extracts

Yong Zhao, Oliver Gericke, Tuo Li, Louise Kjaerulff, Kenneth T. Kongstad, Allison Maree Heskes, Birger Lindberg Møller, Flemming Steen Jørgensen, Henrietta Venter, Sonia Coriani, Susan J. Semple, Dan Staerk*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

5 Citations (Scopus)
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Abstract

Discovery of sustainable and benign-by-design drugs to combat emerging health pandemics calls for new analytical technologies to explore the chemical and pharmacological properties of Nature's unique chemical space. Here, we present a new analytical technology workflow, polypharmacology-labeled molecular networking (PLMN), where merged positive and negative ionization tandem mass spectrometry-based molecular networking is linked with data from polypharmacological high-resolution inhibition profiling for easy and fast identification of individual bioactive constituents in complex extracts. The crude extract of Eremophila rugosa was subjected to PLMN analysis for the identification of antihyperglycemic and antibacterial constituents. Visually easy-interpretable polypharmacology scores and poly pharmacology pie charts as well as microfractionation variation scores of each node in the molecular network provided direct information about each constituent's activity in the seven assays included in this proof-of-concept study. A total of 27 new non canonical nerylneryl diphosphate-derived diterpenoids were identified. Serrulatane ferulate esters were shown to be associated with antihyperglycemic and antibacterial activities, including some showing synergistic activity with oxacillin in clinically relevant (epidemic) methicillin-resistant Staphylococcus aureus strains and some showing saddle-shaped binding to the active site of protein tyrosine phosphatase 1B. PLMN is scalable in the number and types of assays included and thus holds potential for a paradigm shift toward polypharmacological natural-products-based drug discovery.

Original languageEnglish
JournalAnalytical Chemistry
Volume95
Issue number9
Pages (from-to)4381-4389
Number of pages9
ISSN0003-2700
DOIs
Publication statusPublished - 2023

Keywords

  • MAGNETIC-RESONANCE-SPECTROSCOPY
  • NATURAL-PRODUCTS
  • ANTIDIABETIC CONSTITUENTS
  • ABSOLUTE-CONFIGURATION
  • CRUDE EXTRACT
  • EREMOPHILA
  • INHIBITION
  • DITERPENES
  • BIOSYNTHESIS
  • DISCOVERY

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