Evolutionary conservation of influenza A PB2 sequences reveals potential target sites for small molecule inhibitors.

Patel, H. and Kukol, A. 2017. Evolutionary conservation of influenza A PB2 sequences reveals potential target sites for small molecule inhibitors. Virology. 509, pp. 112-120. https://doi.org/10.1016/j.virol.2017.06.009

TitleEvolutionary conservation of influenza A PB2 sequences reveals potential target sites for small molecule inhibitors.
TypeJournal article
AuthorsPatel, H. and Kukol, A.
Abstract

The influenza A basic polymerase protein 2 (PB2) functions as part of a heterotrimer to replicate the viral RNA genome. To investigate novel PB2 antiviral target sites, this work identified evolutionary conserved regions across the PB2 protein sequence amongst all sub-types and hosts, as well as ligand binding hot spots which overlap with highly conserved areas. Fifteen binding sites were predicted in different PB2 domains; some of which reside in areas of unknown function. Virtual screening of ~50,000 drug-like compounds showed binding affinities of up to 10.3 kcal/mol. The highest affinity molecules were found to interact with conserved residues including Gln138, Gly222, Ile529, Asn540 and Thr530. A library containing 1738 FDA approved drugs were screened additionally and revealed Paliperidone as a top hit with a binding affinity of -10 kcal/mol. Predicted ligands are ideal leads for new antivirals as they were targeted to evolutionary conserved binding sites.

Keywordsinfluenza A, PB2, sequence conservation
JournalVirology
Journal citation509, pp. 112-120
ISSN0042-6822
Year2017
PublisherElsevier
Accepted author manuscript
License
CC BY-NC-ND 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1016/j.virol.2017.06.009
PubMed ID28628827
Web address (URL)https://www.sciencedirect.com/science/article/pii/S0042682217301861?via%3Dihub
Publication dates
Published01 Sep 2017

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