title: Inhibitors of tick-borne flavivirus reproduction from structure-based virtual screening.
abstract: Flaviviruses form a large family of enveloped viruses affecting millions of people over the world. To date, no specific therapy was suggested for the infected people, making the treatment exclusively symptomatic. Several attempts were performed earlier for the design of fusion inhibitors for mosquito-borne flaviviruses, whereas for the tick-borne flaviviruses such design had not been performed. We have constructed homology models of envelope glycoproteins of tick-transmitted flaviviruses with the detergent binding pocket in the open state. Molecular docking of substituted 1,4-dihydropyridines and pyrido[2,1-b][1,3,5]thiadiazines was made against these models, and 89 hits were selected for the in vitro experimental evaluation. Seventeen compounds showed significant inhibition against tick-borne encephalitis virus, Powassan virus, or Omsk hemorrhagic fever virus in the 50% plaque reduction test in PEK cells. These compounds identified through rational design are the first ones possessing reproduction inhibition activity against tick-borne flaviviruses.
authors.affiliation: Department of Chemistry, Lomonosov Moscow State University , Moscow 119991, Russia ; FSBI Chumakov Institute of Poliomyelitis and Viral Encephalitides RAMS , Moscow 142782, Russia ; iSCALARE Laboratory, Moscow Institute of Physics and Technology , Dolgoprudny 141700, Russia.
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Osolodkin
authors.affiliation: FSBI Chumakov Institute of Poliomyelitis and Viral Encephalitides RAMS , Moscow 142782, Russia.
authors.forename: Liubov I
authors.initials: LI
authors.lastname: Kozlovskaya
authors.affiliation: Department of Chemistry, Lomonosov Moscow State University , Moscow 119991, Russia ; FSBI Chumakov Institute of Poliomyelitis and Viral Encephalitides RAMS , Moscow 142782, Russia ; iSCALARE Laboratory, Moscow Institute of Physics and Technology , Dolgoprudny 141700, Russia.
authors.forename: Evgenia V
authors.initials: EV
authors.lastname: Dueva
authors.affiliation: ChemEx Laboratory, Vladimir Dal' East Ukrainian National University , Lugansk 91034, Ukraine.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Dotsenko
authors.affiliation: FSBI Chumakov Institute of Poliomyelitis and Viral Encephalitides RAMS , Moscow 142782, Russia.
authors.forename: Yulia V
authors.initials: YV
authors.lastname: Rogova
authors.affiliation: ChemEx Laboratory, Vladimir Dal' East Ukrainian National University , Lugansk 91034, Ukraine.
authors.forename: Konstantin A
authors.initials: KA
authors.lastname: Frolov
authors.affiliation: ChemEx Laboratory, Vladimir Dal' East Ukrainian National University , Lugansk 91034, Ukraine.
authors.forename: Sergey G
authors.initials: SG
authors.lastname: Krivokolysko
authors.affiliation: Department of Chemistry, Lomonosov Moscow State University , Moscow 119991, Russia.
authors.forename: Ekaterina G
authors.initials: EG
authors.lastname: Romanova
authors.affiliation: Department of Chemistry, Lomonosov Moscow State University , Moscow 119991, Russia.
authors.forename: Alexey S
authors.initials: AS
authors.lastname: Morozov
authors.affiliation: FSBI Chumakov Institute of Poliomyelitis and Viral Encephalitides RAMS , Moscow 142782, Russia ; Department of Biology, Lomonosov Moscow State University , Moscow 119991, Russia.
authors.forename: Galina G
authors.initials: GG
authors.lastname: Karganova
authors.affiliation: Department of Chemistry, Lomonosov Moscow State University , Moscow 119991, Russia ; iSCALARE Laboratory, Moscow Institute of Physics and Technology , Dolgoprudny 141700, Russia.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Palyulin
authors.affiliation: iSCALARE Laboratory, Moscow Institute of Physics and Technology , Dolgoprudny 141700, Russia.
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Pentkovski
authors.affiliation: Department of Chemistry, Lomonosov Moscow State University , Moscow 119991, Russia ; iSCALARE Laboratory, Moscow Institute of Physics and Technology , Dolgoprudny 141700, Russia.
authors.forename: Nikolay S
authors.initials: NS
authors.lastname: Zefirov
keywords: 1,4-dihydropyridines; Antiviral compounds; flavivirus; pyrido[2,1-b][1,3,5]thiadiazines