Počet záznamů: 1  

An all-atom, active site exploration of antiviral drugs that target Flaviviridae polymerases

  1. 1.
    0468801 - BC-A 2017 RIV GB eng J - Článek v odborném periodiku
    Valdés, James J. - Gil, V.A. - Butterill, Philip T. - Růžek, Daniel
    An all-atom, active site exploration of antiviral drugs that target Flaviviridae polymerases.
    Journal of General Virology. Roč. 97, OCT (2016), s. 2552-2565. ISSN 0022-1317
    Grant CEP: GA MŠk(CZ) EE2.3.30.0032; GA ČR GB14-36098G; GA MZd(CZ) NV16-34238A
    GRANT EU: European Commission(XE) 316304 - MODBIOLIN
    Institucionální podpora: RVO:60077344
    Klíčová slova: dependent RNA-polymerase * c virus polymerase * de-novo initiation * hepatitis C * allosteric inhibitors * nucleoside inhibitors * molecular dynamics * encephalitis virus * protein-structure * cluster-analysis
    Kód oboru RIV: EE - Mikrobiologie, virologie
    Impakt faktor: 2.838, rok: 2016

    Natural 2'-modified nucleosides are the most widely used antiviral therapy. In their triphosphorylated form, also known as nucleotide analogues, they target the active site of viral polymerases. Viral polymerases have an overall right-handed structure that includes the palm, fingers and thumb domains. These domains are further subdivided into structurally conserved motifs A-G, common to all viral polymerases. The structural motifs encapsulate the allosteric/initiation (N1) and orthosteric/catalytic (N2) nucleotide-binding sites. The current study investigated how nucleotide analogues explore the N2 site of viral polymerases from three genera of the family Flaviviridae using a stochastic, biophysical, Metropolis Monte Carlo-based software. The biophysical simulations showed a statistical distinction in nucleotide-binding energy and exploration between phylogenetically related viral polymerases. This distinction is clearly demonstrated by the respective analogue contacts made with conserved viral polymerase residues, the heterogeneous dynamics of structural motifs, and the orientation of the nucleotide analogues within the N2 site. Being able to simulate what occurs within viral-polymerase-binding sites can prove useful in rational drug designs against viruses.
    Trvalý link: http://hdl.handle.net/11104/0266622