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Virology. 2017 Jun 16;509:112-120. doi: 10.1016/j.virol.2017.06.009. [Epub ahead of print]
Evolutionary conservation of influenza A PB2 sequences reveals potential target sites for small molecule inhibitors.
Patel H1, Kukol A2.
Author information
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 -10.3kcal/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 was screened additionally and revealed Paliperidone as a top hit with a binding affinity of -10kcal/mol. Predicted ligands are ideal leads for new antivirals as they were targeted to evolutionary conserved binding sites.
Copyright ? 2017. Published by Elsevier Inc.
KEYWORDS:
Binding site; Conservation; Drug discovery; Influenza A; PB2; Paliperidone; Sequence evolution; Virtual screening
PMID: 28628827 DOI: 10.1016/j.virol.2017.06.009
Evolutionary conservation of influenza A PB2 sequences reveals potential target sites for small molecule inhibitors.
Patel H1, Kukol A2.
Author information
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 -10.3kcal/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 was screened additionally and revealed Paliperidone as a top hit with a binding affinity of -10kcal/mol. Predicted ligands are ideal leads for new antivirals as they were targeted to evolutionary conserved binding sites.
Copyright ? 2017. Published by Elsevier Inc.
KEYWORDS:
Binding site; Conservation; Drug discovery; Influenza A; PB2; Paliperidone; Sequence evolution; Virtual screening
PMID: 28628827 DOI: 10.1016/j.virol.2017.06.009