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

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.

Structural Genomics of SARS-CoV-2 Indicates Evolutionary Conserved Functional Regions of Viral Proteins

“…The structural analysis of the modeled proteins combined with the sequence conservation analysis revealed several findings. First, we found that the mutated residues tended to locate on the protein's surface, supporting previous observations in other families of RNA viruses that the core residues of viral proteins were more conserved than the surface residues [49,69,70]. Furthermore, in a substantial number of proteins, distributions of mutated positions exhibited spatial patterns, with groups of mutations found to form clusters on the protein surfaces ( Figure 2).…”

Structural genomics and interactomics of 2019 Wuhan novel coronavirus, 2019-nCoV, indicate evolutionary conserved functional regions of viral proteins

“…The structural analysis of the modeled proteins combined with the sequence conservation analysis revealed several findings. First, we found that the mutated residues tend to locate on the protein's surface, supporting the previous observations in other families of RNA viruses that the core residues of viral proteins are more conserved than the surface residues [48,56,57]. Furthermore, in a substantial number of proteins, distributions of mutated positions exhibited spatial patterns, with groups of mutations found to form clusters on the protein surfaces ( Fig.2).…”

Structural Genomics and Interactomics of 2019 Wuhan Novel Coronavirus, SARS-CoV-2, Indicate Evolutionary Conserved Functional Regions of Viral Proteins

“…The structural analysis of the modeled proteins combined with the sequence conservation analysis revealed several findings. First, we found that the mutated residues tend to locate on the protein's surface, supporting previous observations in other families of RNA viruses that the core residues of viral proteins are more conserved than the surface residues [48,56,57]. Furthermore, in a substantial number of proteins, distributions of mutated positions exhibited spatial patterns, with groups of mutations found to form clusters on the protein surfaces ( Fig.2).…”