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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F16%3AN0000037" target="_blank" >RIV/00027162:_____/16:N0000037 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/60077344:_____/16:00468801 RIV/60076658:12310/16:43891958

Výsledek na webu

<a href="http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/jgv.0.000569" target="_blank" >http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/jgv.0.000569</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1099/jgv.0.000569" target="_blank" >10.1099/jgv.0.000569</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

Natural 2'-modified nucleosides are the most widely used antiviral therapy. In their triphosphorylated form, a.k.a. nucleotide analogues target the active site of viral polymerases. Viral polymerases have an overall right handed structure that include 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 Flaviviridae family 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.

Název v anglickém jazyce

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

Popis výsledku anglicky

Natural 2'-modified nucleosides are the most widely used antiviral therapy. In their triphosphorylated form, a.k.a. nucleotide analogues target the active site of viral polymerases. Viral polymerases have an overall right handed structure that include 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 Flaviviridae family 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.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

EE - Mikrobiologie, virologie

OECD FORD obor

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Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of General Virology

ISSN

0022-1317

e-ISSN

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Svazek periodika

97

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

14

Strana od-do

2552-2565

Kód UT WoS článku

000386872100009

EID výsledku v databázi Scopus

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