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

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
59 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)112-120
Number of pages9
JournalVirology
Volume509
Early online date17 Jun 2017
DOIs
Publication statusPublished - 1 Sept 2017

Fingerprint

Dive into the research topics of 'Evolutionary conservation of influenza A PB2 sequences reveals potential target sites for small molecule inhibitors'. Together they form a unique fingerprint.

Cite this