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Tick-borne encephalitis virus (TBEV) is a typical member of Flavivirus genus, which also includes such important for public health human pathogens as dengue virus, West Nile virus, yellow fever virus, and Zika virus. TBEV is transmitted during the bite of an infected tick and may cause tick-borne encephalitis (TBE), which leads to serious neurological consequences, disabilities or death. Despite availability of vaccines, thousands of TBE cases are registered annually, thus justifying the need for alternative treatment schemes based on small molecule drugs. Due to significant similarity of pathogens throughout the Flavivirus genus, these drugs can be potentially repurposed for the treatment of other flaviviral diseases. Target-based discovery of TBEV reproduction inhibitors is mainly based on molecular docking against homology models of structural and non-structural proteins due to limited availability of data. When we started this work, no data were available at all, and blind docking was the only reasonable scheme to confine the chemical space of possible antivirals. The envelope protein E of TBEV was chosen as the main target, because it has a well-developed binding site for possible inhibitors and allows to drift away from more common scaffolds such as peptide or nucleoside analogues. This strategy appeared to be working and led to identification of small molecules (1,4-dihydropyridines and 1,3,5-thiadiazolines) with IC50 values on two-digit nanomolar level [1]. Further studies based on different scaffolds allowed us to identify two more classes of highly efficient reproduction inhibitors of TBEV, 4-aminotetrahydroquinazolines and rigid amphipathic nucleosides with perylene moieties [2,3]. Therefore, anti-TBEV molecules started to shape and position itself in the antiviral drug-target space [4]. According to the time-of-addition studies, these molecules presumably interact with the viral envelope and may function as fusion inhibitors. These data supported our intention to rationalize the interaction of the small molecules with the E proteins via molecular dynamics simulations. The interaction between the small molecule inhibitors and envelope protein was studied in a simple system with implicit solvent [5], showing the shift of protein movement pattern to resemble less stable variants of TBEV [6]. Apparently, fusion inhibition has a mechanical nature in flaviviruses, and small molecule inhibitors of this process impair the low pH dependent conformational rearrangements of E proteins similarly to a scotch block. This idea partially explains the lack of clear structure-activity relationships in the series. More advanced modelling became possible with the release of a high resolution cryo-EM structure of dengue virus, which allowed to study the interactions between the envelope proteins and the membrane in the homology model of TBEV envelope heterotetrameric building block, consisting of two E and two M protein subunits. This model allowed to study the very initial stages of the conformational rearrangements occurring upon the protonation of histidine residues, forming the so-called 'histidine switch'. Five hundred nanoseconds simulations showed that certain conserved clusters of positively charged residues are destabilized after the histidine protonation, presumably initiating the more pronounced movements. The humic substances have also shown antiviral activity against TBEV. As they are complex mixtures characterised by brutto formulas and distrubutions of atom types, chemoinformatic approaches are useful to identify possible active ingredients in these mixtures, which can be further synthesised and tested for antiviral activity. Approaches used for generation of the structural formulas of active components will be presented.