TY - JOUR
T1 - Polypharmacology-labeled molecular networking
T2 - An analytical technology workflow for accelerated identification of multiple bioactive constituents in complex extracts
AU - Zhao, Yong
AU - Gericke, Oliver
AU - Li, Tuo
AU - Kjaerulff, Louise
AU - Kongstad, Kenneth T.
AU - Heskes, Allison Maree
AU - Møller, Birger Lindberg
AU - Jørgensen, Flemming Steen
AU - Venter, Henrietta
AU - Coriani, Sonia
AU - Semple, Susan J.
AU - Staerk, Dan
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - MAGNETIC-RESONANCE-SPECTROSCOPY
KW - NATURAL-PRODUCTS
KW - ANTIDIABETIC CONSTITUENTS
KW - ABSOLUTE-CONFIGURATION
KW - CRUDE EXTRACT
KW - EREMOPHILA
KW - INHIBITION
KW - DITERPENES
KW - BIOSYNTHESIS
KW - DISCOVERY
U2 - 10.1021/acs.analchem.2c04859
DO - 10.1021/acs.analchem.2c04859
M3 - Journal article
C2 - 36802535
VL - 95
SP - 4381
EP - 4389
JO - Industrial And Engineering Chemistry Analytical Edition
JF - Industrial And Engineering Chemistry Analytical Edition
SN - 0003-2700
IS - 9
ER -