Examination of molecular space and feasible structures of bioactive components of humic substances by FTICR MS data mining in ChEMBL database

Abstract

Humic substances (HS) are complex natural mixtures comprising a large variety of compounds produced during decomposition of decaying biomass. The molecular composition of HS is extremely diverse as it was demonstrated with the use of high resolution mass spectrometry. The building blocks of HS are mostly represented by plant-derived biomolecules (lignins, lipids, tannins, carbohydrates, etc.). As a result, HS show a wide spectrum of biological activity. Despite that, HS remain a ‘biological activity black-box’ due to unknown structures of constituents responsible for the interaction with molecular targets. In this study, we investigated the antiviral activity of eight HS fractions isolated from peat and coal, as well as of two synthetic humic-like materials. We determined molecular compositions of the corresponding samples using ultra-high resolution Fourier-transform ion cyclotron resonance mass-spectrometry (FTICR MS). Inhibitory activity of HS was studied with respect to reproduction of tick-borne encephalitis virus (TBEV), which is a representative of Flavivirus genus, and to a panel of enteroviruses (EVs). The samples of natural HS inhibited TBEV reproduction already at a concentration of 1 µg/mL, but they did not inhibit reproduction of EVs. We found that the total relative intensity of FTICR MS formulae within elemental composition range commonly attributed to flavonoid-like structures is correlating with the activity of the samples. In order to surmise on possible active structural components of HS, we mined formulae within FTICR MS assignments in the ChEMBL database. Out of 6502 formulae within FTICR MS assignments, 3852 were found in ChEMBL. There were more than 71 thousand compounds related to these formulae in ChEMBL. To support chemical relevance of these compounds to natural HS we applied the previously developed approach of selective isotopic exchange coupled to FTICR MS to obtain structural information on the individual components of HS. This enabled to propose compounds from ChEMBL, which corroborated the labeling data. The obtained results provide the first insight onto the possible structures, which comprise antiviral components of HS and, respectively, can be used for further disclosure of antiviral activity mechanism of HS.

Antiviral activity of natural humic substances and shilajit materials against HIV-1: Relation to structure

“…For characterization of molecular space of the set of HS samples used in this study the previously published FTICR mass-spectrometric data (peak lists) were used for CHA-G, CHA-P, CHA-S, PelHA, PelHMA, PekFA, PHA-5, PFA-5, MHQ-FA were used ( Orlov et al, 2019 , Zhernov et al, 2017 ). Mass-spectrum of the Shelajit sample Sh1 was obtained using 7T FTICR MS Apex Ultra (Bruker Daltonics, Germaby) equipped with the harmonized cell ( Nikolaev et al, 2011 ) and electrospray ionization (ESI) source operating in negative ion mode.…”

“…Humic substances (HS) have been known for a long time for their antiviral activity ( Helbig et al 1997 , Klöcking et al, 2002 ). The different fractions of natural HS and synthetic HS-like materials are active against HIV ( Botes et al 2002 , Brucolleri et al 2013 , Kornilaeva et al 2019 , Zhernov et al 2017 , Zhernov, 2018 ), influenza virus A/WSN/1933 (H1N1) ( Lu et al, 2002 ), herpes simplex virus-1 (HSV-1) ( Klöcking et al, 2002 ), Coxsackie virus A9 ( Klöcking et al, 1972 ), tick-borne encephalitis virus (TBEV) ( Orlov et al, 2019 ).…”

Contributions to Lignomics: Stochastic Generation of Oligomeric Lignin Structures for Interpretation of MALDI–FT‐ICR‐MS Results

“…For each MS peak, two potentialc andidates are proposed because FT-ICR MS alone cannot distinguish between isomers. [16,98] Other assignments are certainly imaginable outside of the two that are given for each peak. At otal of 30 peaks from the low mass cluster,3 0peaks from the middle mass cluster,a nd 20 peaks from the high mass cluster are used (roughlyb ased on the relative contribution of each cluster to the whole spectrum).…”

“…As previously mentioned, one significant limitation of FT-ICR MS analysisa lone is its inability to distinguish betweeni somers. [16,98] To overcome this hurdle, both experimental and computational approaches may be explored.E xperimentally, the utilization of separation techniques (such as liquid chromatography) and hybridized or tandem MS analyses shows promise. [99][100][101][102][103] For example, Leyva et al utilized electrospray ionization-trapped ion mobility-FT-ICR MS/MS to obtain an estimate of structurala nd conformational isomers in analyzed dissolved organic matter.…”

“…[6] Unlike cellulose, which has am ore regular and ordered structure, [9,10] the diversity of lignins from contrasting sources coupled with its intramolecular heterogeneity presents au nique challenge regarding its characterization. [7,[11][12][13] This type of analysisi sw idely relevant across many fields of study.Lignin is aprimary geochemical precursor to coal, [14] am ajor component of dissolved organic matter [15] and humic substances, [16] and an important potentialf eedstock for green fuels and chemicals. [17] The main structuralf eatures of monomers in ag iven lignin polymer are summarized in Figure 1.…”