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

SYSNO ASEP	0468801
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	An all-atom, active site exploration of antiviral drugs that target Flaviviridae polymerases
Author(s)	Valdés, James J. (BC-A)_{RID, ORCID} Gil, V.A. (ES) Butterill, Philip T. (BC-A)_{RID, ORCID} Růžek, Daniel (BC-A)_{RID, ORCID}
Number of authors	4
Source Title	Journal of General Virology. - : Microbiology Society - ISSN 0022-1317 Roč. 97, OCT (2016), s. 2552-2565
Number of pages	14 s.
Publication form	Print - P
Language	eng - English
Country	GB - United Kingdom
Keywords	dependent RNA-polymerase ; c virus polymerase ; de-novo initiation ; hepatitis C ; allosteric inhibitors ; nucleoside inhibitors ; molecular dynamics ; encephalitis virus ; protein-structure ; cluster-analysis
Subject RIV	EE - Microbiology, Virology
R&D Projects	EE2.3.30.0032 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	GB14-36098G GA ČR - Czech Science Foundation (CSF)
	NV16-34238A GA MZd - Ministry of Health (MZ)
Institutional support	BC-A - RVO:60077344
UT WOS	000386872100009
EID SCOPUS	84991609152
DOI	10.1099/jgv.0.000569
Annotation	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.
Workplace	Biology Centre (since 2006)
Contact	Dana Hypšová, eje@eje.cz, Tel.: 387 775 214
Year of Publishing	2017

Number of the records: 1