Deciphering bioactive compounds of complex natural products by tandem mass spectral molecular networking combined with an aggregation-induced emission based probe

Zhenzhong Yang; Jun Li; Xuechun Chen; Xiaoping Zhao; Yi Wang

doi:10.1016/j.jpha.2020.11.007

Volume 12 Issue 1

Feb. 2022

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Article Navigation > Journal of Pharmaceutical Analysis > 2022 > 12(1): 129-135

Zhenzhong Yang, Jun Li, Xuechun Chen, Xiaoping Zhao, Yi Wang. Deciphering bioactive compounds of complex natural products by tandem mass spectral molecular networking combined with an aggregation-induced emission based probe[J]. Journal of Pharmaceutical Analysis, 2022, 12(1): 129-135. doi: 10.1016/j.jpha.2020.11.007

Citation:

Zhenzhong Yang, Jun Li, Xuechun Chen, Xiaoping Zhao, Yi Wang. Deciphering bioactive compounds of complex natural products by tandem mass spectral molecular networking combined with an aggregation-induced emission based probe[J]. Journal of Pharmaceutical Analysis, 2022, 12(1): 129-135. doi: 10.1016/j.jpha.2020.11.007

Citation:

Zhenzhong Yang, Jun Li, Xuechun Chen, Xiaoping Zhao, Yi Wang. Deciphering bioactive compounds of complex natural products by tandem mass spectral molecular networking combined with an aggregation-induced emission based probe[J]. Journal of Pharmaceutical Analysis, 2022, 12(1): 129-135. doi: 10.1016/j.jpha.2020.11.007

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Deciphering bioactive compounds of complex natural products by tandem mass spectral molecular networking combined with an aggregation-induced emission based probe

doi: 10.1016/j.jpha.2020.11.007

a. Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China;
b. College of Preclinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China

Funds:

This work was financially supported by the National Key R&

D Program of China (Grant No.: 2018YFC1704502), the National Natural Science Foundation of China (Grant No.: 81603268), and the National Natural Science Foundation of China (Grant No.: 81822047).

Received Date: Nov. 23, 2019
Accepted Date: Nov. 24, 2020
Rev Recd Date: Nov. 16, 2020
Publish Date: Nov. 28, 2020

Abstract

Abstract

Natural products are great treasure troves for the discovery of bioactive components. Current bioassay guided fractionation for identification of bioactive components is time- and workload-consuming. In this study, we proposed a robust and convenient strategy for deciphering the bioactive profile of natural products by mass spectral molecular networking combined with rapid bioassay. As a proof-of-concept, the strategy was applied to identify angiotensin converting enzyme (ACE) inhibitors of Fangjihuangqi decoction (FJHQD), a traditional medicine clinically used for the treatment of heart failure. The chemical profile of FJHQD was comprehensively revealed with the assistance of tandem mass spectral molecular networking, and a total of 165 compounds were identified. With characterized constituents, potential clinical applications of FJHQD were predicted by Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine, and a range of cardiovascular related diseases were significantly enriched. ACE inhibitory activities of FJHQD and its constituents were then investigated with an aggregation-induced emission based fluorescent probe. FJHQD exhibited excellent ACE inhibitory effects, and a bioactive molecular network was established to elucidate the ACE inhibitory profile of constituents in FJHQD. This bioactive molecular network provided a panoramic view of FJHQD's ACE inhibitory activities, which demonstrated that flavones from Astragali Radix and Glycyrrhizae Radix et Rhizoma, saponins from Astragali Radix, and sesquiterpenoids from Atractylodis Macrocephalae Rhizoma were principal components responsible for this effect of FJHQD. Among them, four novel ACE inhibitors were the first to be reported. Our study indicated that the proposed strategy offers a useful approach to uncover the bioactive profile of traditional medicines and provides a pragmatic workflow for exploring bioactive components.
- Bioactive profile,
- Bioactive molecular network,
- Fangjihuangqi decoction,
- Angiotensin converting enzyme inhibitors

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References(71)

References

Y.Y. Tu, The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine, Nat. Med., 17(2011)1217-1220

E. Patridge, P. Gareiss, M.S. Kinch, et al., An analysis of FDA-approved drugs:natural products and their derivatives, Drug Discov. Today, 21(2016)204-207

Z. Yang, Y. Wang, Y. Wang, et al., Bioassay-guided screening and isolation of alpha-glucosidase and tyrosinase inhibitors from leaves of Morus alba, Food Chem., 131(2012)617-625

Z. Yang, Z. Li, Z. Li, DPPH-HPLC-MS assisted rapid identification of endothelial protective substances from Xiao-Ke-An, J. Ethnopharmacol., 211(2018)188-196

Z. Yang, J. Zhu, H. Zhang, et al., Investigating chemical features of Panax notoginseng based on integrating HPLC fingerprinting and determination of multiconstituents by single reference standard, J. Ginseng Res., 42(2018)334-342

L. Ory, E.H. Nazih, S. Daoud, et al., Targeting bioactive compounds in natural extracts-development of a comprehensive workflow combining chemical and biological data, Anal. Chim. Acta, 1070(2019)29-42

Z. Yang, H. Tang, Q. Shao, et al., Enrichment and purification of the bioactive flavonoids from flower of abelmoschus manihot (L.) medic using macroporous resins, Molecules, 23(2018)

L.-F. Nothias, M. Nothias-Esposito, R. da Silva, et al., Bioactivity-based molecular networking for the discovery of drug leads in natural product bioassay-guided fractionation, J. Nat. Prod., 81(2018)758-767

M. Yang, J.H. Sun, Z.Q. Lu, et al., Phytochemical analysis of traditional Chinese medicine using liquid chromatography coupled with mass spectrometry, J. Chromatogr. A, 1216(2009)2045-2062

Z.H. Li, X.M. Guo, Z.L. Cao, et al., New MS network analysis pattern for the rapid identification of constituents from traditional Chinese medicine prescription Lishukang capsules in vitro and in vivo based on UHPLC/Q-TOF-MS, Talanta, 189(2018)606-621

X. Zhang, L. Gao, Z. Zhang, et al., Separation and determination of acetyl-glutamine enantiomers by HPLC-MS and its application in pharmacokinetic study, J. Pharm. Anal., 7(2017)303-308

K.T. Johansen, S.G. Wubshet, N.T. Nyberg, HPLC-NMR revisited:using time-slice high-performance liquid chromatography-solid-phase extraction-nuclear magnetic resonance with database-assisted dereplication, Anal. Chem., 85(2013)3183-3189

M.L. Chen, W.Q. Chang, J.L. Zhou, et al., Comparison of three officinal species of Callicarpa based on a biochemome profiling strategy with UHPLC-IT-MS and chemometrics analysis, J. Pharmaceut. Biomed. Anal., 145(2017)666-674

H.Q. Pang, H.M. An, H. Yang, et al., Comprehensive chemical profiling of Yindan Xinnaotong soft capsule and its neuroprotective activity evaluation in vitro, J. Chromatogr. A, 1601(2019)288-299

R. Nikzad-Langerodi, S. Ortmann, E.M. Pferschy-Wenzig, et al., Assessment of anti-inflammatory properties of extracts from Honeysuckle (Lonicera sp L., Caprifoliaceae) by ATR-FTIR spectroscopy, Talanta, 175(2017)264-272

R.-Z. Liu, R. Wang, H.-M. An, et al., A strategy for screening bioactive components from natural products based on two-dimensional cell membrane chromatography and component-knockout approach, J. Chromatogr. A, 1601(2019)171-177

M. Liao, H. Shang, Y. Li, et al., An integrated approach to uncover quality marker underlying the effects of Alisma orientale on lipid metabolism, using chemical analysis and network pharmacology, Phytomedicine, 45(2018)93-104

Z. Yang, Q. Shao, Z. Ge, et al., A bioactive chemical markers based strategy for quality assessment of botanical drugs:xuesaitong injection as a case study, Sci. Rep., 7(2017)2410

Y. Zhong, J. Zhu, Z. Yang, et al., Q-marker based strategy for CMC research of Chinese medicine:a case study of Panax Notoginseng saponins, Phytomedicine, 44(2018)129-137

J. Zhu, Z. Yang, Rapid quantitative determination of main saponin constituents in Panax notoginseng by near-infrared spectroscopy technique, Chin. J. Mod. Appl. Pharm., 34(2017)1007-1010

M. Metra, J.R. Teerlink, Heart failure, Lancet, 390(2017)1981-1995

P. Rossignol, A.F. Hernandez, S.D. Solomon, et al., Heart failure drug treatment, Lancet, 393(2019)1034-1044

J.A. Kane, J.K. Kim, S.A. Haidry, et al., Discontinuation/dose reduction of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers during acute decompensated heart failure in african-American patients with reduced left-ventricular ejection fraction, Cardiology, 137(2017)121-125

M. Tsuboi, R. Sada, Angiotensin-converting-enzyme inhibitor-induced intestinal angioedema, Intern. Med., 54(2015)3247-3247

S. Laurent, Antihypertensive drugs, Pharmacol. Res., 124(2017)116-125

M. Regulski, K. Regulska, B.J. Stanisz, et al., Chemistry and pharmacology of angiotensin-converting enzyme inhibitors, Curr. Pharmaceut. Des., 21(2015)1764-1775

X. Wang, X. Liu, C. Xia, et al., Research progress in chemical constituents in single herbs of Fangji Huangqi Decoction and its pharmacological activities, Chin. Trad. Herb. Drugs, 47(2016)3527-3534

H. Yang, W. Liu, Y. Wu, et al., Analysis on regularity of drug-syndrome of Fangji Huangqi Decoction in modern clinical application, Chin. J. Trad. Chin. Med. Pharm., 31(2016)3041-3044

X. Wang, X. Liu, T. Zhu, et al., Development and validation of an UHPLC-QqQ-MS technique for simultaneous determination of ten bioactive components in fangji huangqi tang, J. Anal. Methods Chem., 2016(2016)

X. Wang, X. Liu, X. Xu, et al., Screening and identification of multiple constituents and their metabolites of Fangji Huangqi Tang in rats by ultra-high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry basing on coupling data processing techniques, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 985(2015)14-28

M. Wang, J.J. Carver, V.V. Phelan, et al., Sharing and community curation of mass spectrometry data with global natural products social molecular networking, Nat. Biotechnol., 34(2016)828-837

H. Wang, Y. Huang, X. Zhao, et al., A novel aggregation-induced emission based fluorescent probe for an angiotensin converting enzyme (ACE) assay and inhibitor screening, Chem. Commun., 50(2014)15075-15078

Z. Liu, F. Guo, Y. Wang, et al., BATMAN-TCM:a bioinformatics analysis tool for molecular mechANism of traditional Chinese medicine, Sci. Rep., 6(2016)

J. Xiao, N. Song, T. Lu, et al., Rapid characterization of TCM Qianjinteng by UPLC-QTOF-MS and its application in the evaluation of three species of Stephania, J. Pharmaceut. Biomed. Anal., 156(2018)284-296

B. Zhu, Q.L. Zhang, J.W. Hua, et al., The traditional uses, phytochemistry, and pharmacology of Atractylodes macrocephala Koidz.:a review, J. Ethnopharmacol., 226(2018)143-167

P.-j. Xie, F. You, L.-x. Huang, et al., Comprehensive assessment of phenolic compounds and antioxidant performance in the developmental process of jujube (Ziziphus jujuba Mill.), J. Funct. Food., 36(2017)233-242

S.H. Choi, J.B. Ahn, N. Kozukue, et al., Distribution of free amino acids, flavonoids, total phenolics, and antioxidative activities of Jujube (Ziziphus jujuba) fruits and seeds harvested from plants grown in Korea, J. Agric. Food Chem., 59(2011)6594-6604

W. Li, K. Koike, Y. Asada, et al., Flavonoids from Glycyrrhiza pallidiflora hairy root cultures, Phytochemistry, 60(2002)351-355

D.K. Semwal, R. Badoni, R. Semwal, et al., The genus Stephania (Menispermaceae):chemical and pharmacological perspectives, J. Ethnopharmacol., 132(2010)369-383

M. Ota, F. Xu, Y.L. Li, et al., Comparison of chemical constituents among licorice, roasted licorice, and roasted licorice with honey, J. Nat. Med., 72(2018)80-95

L. Montero, E. Ibanez, M. Russo, et al., Metabolite profiling of licorice (Glycyrrhiza glabra) from different locations using comprehensive two-dimensional liquid chromatography coupled to diode array and tandem mass spectrometry detection, Anal. Chim. Acta, 913(2016)145-159

Z. Sun, J. Shao, M. Guo, A review on chemical components and pharmacological effects of Huangqi, Clin. J. Chin. Med, 7(2015)22-25

G. Rizzato, E. Scalabrin, M. Radaelli, et al., A new exploration of licorice metabolome, Food Chem., 221(2017)959-968

J. Wang, J. Li, X. Wu, et al., Assessment of genetic fidelity and composition:mixed elicitors enhance triterpenoid and flavonoid biosynthesis of Glycyrrhiza uralensis Fisch. tissue cultures, Biotechnol. Appl. Biochem., 64(2017)211-217

N. Martins, L. Barros, M. Duenas, et al., Characterization of phenolic compounds and antioxidant properties of Glycyrrhiza glabra L. rhizomes and roots, RSC Advances, 5(2015)26991-26997

L. Long, L. Wang, S. Qi, et al., New sesquiterpenoid glycoside from the rhizomes of Atractylodes lancea, Nat. Prod. Res.,(2019)1-8

J. Zhang, X.J. Xu, W. Xu, et al., Rapid characterization and identification of flavonoids in radix Astragali by ultra-high-pressure liquid chromatography coupled with linear ion trap-orbitrap mass spectrometry, J. Chromatogr. Sci., 53(2015)945-952

W. Song, L. Si, S. Ji, et al., Uralsaponins M-Y, antiviral triterpenoid saponins from the roots of Glycyrrhiza uralensis, J. Nat. Prod., 77(2014)1632-1643

I.R. Kubra, L.J. Rao, An impression on current developments in the technology, chemistry, and biological activities of ginger (Zingiber officinale Roscoe), Crit. Rev. Food Sci. Nutr., 52(2012)651-688

T. Xu, M. Yang, Y. Li, et al., An integrated exact mass spectrometric strategy for comprehensive and rapid characterization of phenolic compounds in licorice, Rapid Commun. Mass Spectrom., 27(2013)2297-2309

L. Shan, N. Yang, Y. Zhao, et al., A rapid classification and identification method applied to the analysis of glycosides in Bupleuri radix and liquorice by ultra high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry, J. Separ. Sci., 41(2018)3791-3805

T. Fujimaki, S. Saiki, E. Tashiro, et al., Identification of licopyranocoumarin and glycyrurol from herbal medicines as neuroprotective compounds for Parkinson's disease, PloS One, 9(2014) e100395

W. Song, X. Qiao, K. Chen, et al., Biosynthesis-based quantitative analysis of 151 secondary metabolites of licorice to differentiate medicinal Glycyrrhiza species and their hybrids, Anal. Chem., 89(2017)3146-3153

Q. Zhang, M. Ye, Chemical analysis of the Chinese herbal medicine Gan-Cao (licorice), J. Chromatogr., A, 1216(2009)1954-1969

X. Li, H. Liu, Y. Shao, et al., Wide Identification of the Compounds in Licorice and Exploration of the Mechanism for Prostatitis Treatment by Combining UHPLC-LTQ-Orbitrap MS with Network Pharmacology, ChemistrySelect, 4(2019)3011-3017

H. Jiang, B.N. Timmermann, D.R. Gang, Characterization and identification of diarylheptanoids in ginger (Zingiber officinale Rosc.) using high-performance liquid chromatography/electrospray ionization mass spectrometry, Rapid Commun. Mass Spectrom., 21(2007)509-518

Q. Zhang, M. Ye, Chemical analysis of the Chinese herbal medicine Gan-Cao (licorice), J. Chromatogr. A, 1216(2009)1954-1969

C. Schmid, C. Dawid, V. Peters, et al., Saponins from European licorice roots (Glycyrrhiza glabra), J. Nat. Prod., 81(2018)1734-1744

Y. Zhang, Y.-Q. Guo, X.-X. Li, et al., Rearranged oleanane type saponins, astraisoolesaponins A 1-A 3 and B, from the stems of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, Tetrahedron, 72(2016)7008-7013

M. He, H. Wu, J. Nie, et al., Accurate recognition and feature qualify for flavonoid extracts from Liang-wai Gan Cao by liquid chromatography-high resolution-mass spectrometry and computational MS/MS fragmentation, J. Pharmaceut. Biomed. Anal., 146(2017)37-47

X.X. Gao, J.Y. Feng, L. Yang, et al., Investigation on pharmacochemistry and pharmacokinetics of atractylenolides from Atractylodes in vivo based on UPLC-MS combined with everted gut sac model in vitro, J. Liq. Chromatogr. Rel. Technol., 41(2019)892-902

T. Fukai, B.-s. Cai, K. Maruno, et al., An isoprenylated flavanone from Glycyrrhiza glabra and rec-assay of licorice phenols, Phytochemistry, 49(1998)2005-2013

W.Y. Jiang, Therapeutic wisdom in traditional Chinese medicine:a perspective from modern science, Trends Pharmacol. Sci., 26(2005)558-563

R. Xue, Z. Fang, M. Zhang, et al., TCMID:traditional Chinese medicine integrative database for herb molecular mechanism analysis, Nucleic Acids Res., 41(2013) D1089-D1095

Y.H. Li, C.Y. Yu, X.X. Li, et al., Therapeutic target database update 2018:enriched resource for facilitating bench-to-clinic research of targeted therapeutics, Nucleic Acids Res., 46(2018) D1121-D1127

M. Tamargo, J. Tamargo, Future drug discovery in renin-angiotensin-aldosterone system intervention, Expet Opin. Drug Discov., 12(2017)827-848

V.B. Patel, J.-C. Zhong, M.B. Grant, et al., Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure, Circul. Res., 118(2016)1313-1326

A.C. Simoes e Silva, M.M. Teixeira, ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis, Pharmacol. Res., 107(2016)154-162

Z. Ke, Z. Su, X. Zhang, et al., Discovery of a potent angiotensin converting enzyme inhibitor via virtual screening, Bioorg. Med. Chem. Lett, 27(2017)3688-3692

Z. Li, N. Ai, L.X. Yu, et al., A multiple biomarker assay for quality assessment of botanical drugs using a versatile microfluidic chip, Sci. Rep., 7(2017)12243

J. Zhao, P. Yang, F. Li, et al., Therapeutic effects of astragaloside IV on myocardial injuries:multi-target identification and network analysis, PloS One, 7(2012), e44938.

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