Humic substance (HS) is a heterogeneous supramolecular ensemble of natural organic compounds formed by oxidative decomposition of biomacromolecules in soils, coals, waters, etc. Inhibitory effect of HS on reproduction of a wide range of DNA and RNA viruses reveals a possibility to apply HS against human pathogens with no approved therapeutics. However, the exact structural composition of HS can not be determined by modern analytical techniques and structure and the nature of HS bioactivity remains unknown, thus complicating the process of development HS-based drugs. We investigated inhibitory effect of ten HS samples on enteroviruses and flaviviruses in cell-based assays and developed a technique for an active component identification using fourier-transform ion cyclotron resonance mass spectrometry FTICR MS data analysis and chemical database search.<br/>All HS samples inhibited tick-borne encephalitis virus (TBEV) reproduction with EC50 values in range of 0.1-1 μg/ml and exhibited no cytotoxicity up to 10 μg/ml. The same HS samples did not inhibit reproduction of enteroviruses. Observed specificity of the samples was attributed to possible presence of compounds with a specific anti-TBEV activity. Molecular composition of all HS samples was explored by ESI FTICR MS. More than 6.5k unique formulae were identified and spectral data were analysed using van Krevelen diagrams and heatmaps generated based on samples formulae fingerprints. Analysis revealed subtle differences in the formulae composition of samples. Chemoinformatic approach was further employed to identify putative active components structures.<br/>We developed a methodology for identifying active components of HS samples using publicly available data from ChEMBL version 23. Formulae presented in the samples were searched in ChEMBL and related structures and bioactivity entries were retrieved and standardised. Compounds corresponding to formulae present in HS samples are mostly represented by typical natural compounds, such as flavonoids, coumarins, etc. Antiviral activity profiles were analysed for flaviviruses and enteroviruses and several compounds were suggested as potential active components of the HS samples. This methodology can be applied for any mixture of small molecules with known formulae composition and spectrum of bioactivity.

Chemoinformatic approach to identification of antiviral components in humic substances

255th National Meeting (2018)

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