Ticks are small blood-sucking arthropods transmitting a number of viral and bacterial diseases. Despite their rarity, viral tick-borne diseases such as tick-borne encephalitis and Powassan encephalitis cause severe brain pathologies leading to serious disabilities or even death. The only current method to prevent these diseases is vaccination, availability of which is limited. No generally applicable post-infection treatment methods are avialable.We performed a structure-based virtual screening study against detergent-binding pocket in the envelope E proteins of tick-borne flaviviruses. Two compounds were identified with submicromolar activity in the plaque formation inhibition assay against tick-borne encephalitis virus and micromolar activity against Powassan virus [1]. Inhibition of virus entry and haemagglutinating activity was shown for these compounds.Possible binding modes for the replication inhibitors were analysed by means of molecular docking and pocket identification for the pre-fusion dimeric and post-fusion trimeric forms of the envelope proteins. Molecular dynamics simulations allowed us to identify the most favourable conformations of the molecules, which can be utilised for further shape-based search of novel, more effective fusion inhibitors.[1] D.I. Osolodkin, L.I. Kozlovskaya, E.V. Dueva, V.V. Dotsenko, Y.V. Rogova, K.A. Frolov, S.G. Krivokolysko, E.G. Romanova, A.S. Morozov, G.G. Karganova, V.A. Palyulin, V.M. Pentkovski, and N.S. Zefirov. Inhibitors of tick-borne flavivirus reproduction from structure-based virtual screening. ACS Medicinal Chemistry Letters, 2013, 4(9):869�874.

On the way to fusion inhibitors for tick-borne flaviviruses: Identification of lead compounds and mechanism studies

248th National Meeting (2014)

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