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 -