Influenza A nucleoprotein binding sites for antivirals: current research and future potential

This document is the Accepted Manuscript version of the following article: Andreas Kukol and Hershna Patel, ‘Influenza A nucleoprotein binding sites for antivirals: current research and future potential’, Future Biology, Vol 9(7): 625-627, July 2014. The version of record is available online at doi: 10.2217/fvl.14.45Peer reviewedFinal Accepted Versio

Evaluation of a novel virtual screening strategy using receptor decoy binding sites

Virtual screening is used in biomedical research to predict the binding affinity of a large set of small organic molecules to protein receptor targets. This report shows the development and evaluation of a novel yet straightforward attempt to improve this ranking in receptor-based molecular docking using a receptor-decoy strategy. This strategy includes defining a decoy binding site on the receptor and adjusting the ranking of the true binding-site virtual screen based on the decoy-site screen. The results show that by docking against a receptor-decoy site with Autodock Vina, improved Receiver Operator Characteristic Enrichment (ROCE) was achieved for 5 out of fifteen receptor targets investigated, when up to 15 % of a decoy site rank list was considered. No improved enrichment was seen for 7 targets, while for 3 targets the ROCE was reduced. The extent to which this strategy can effectively improve ligand prediction is dependent on the target receptor investigated

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

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

Deformations of thick two-material cylinder under axially varying radial pressure

Stresses and deformations in thick, short, composite cylinder subjected to axially varying radial pressure are studied. Effect of slippage at the interface is examined. In the NASTRAN finite element model, multipoint constraint feature is utilized. Results are compared with theoretical analysis and SAP-IV computer code. Results from NASTRAN computer code are in good agreement with the analytical solutions. Results suggest a considerable influence of interfacial slippage on the axial bending stresses in the cylinder

Search on a Hypercubic Lattice using a Quantum Random Walk: I. d>2

Random walks describe diffusion processes, where movement at every time step is restricted to only the neighbouring locations. We construct a quantum random walk algorithm, based on discretisation of the Dirac evolution operator inspired by staggered lattice fermions. We use it to investigate the spatial search problem, i.e. finding a marked vertex on a $d$-dimensional hypercubic lattice. The restriction on movement hardly matters for $d>2$, and scaling behaviour close to Grover's optimal algorithm (which has no restriction on movement) can be achieved. Using numerical simulations, we optimise the proportionality constants of the scaling behaviour, and demonstrate the approach to that for Grover's algorithm (equivalent to the mean field theory or the $d\to\infty$ limit). In particular, the scaling behaviour for $d=3$ is only about 25% higher than the optimal $d\to\infty$ value.Comment: 11 pages, Revtex (v2) Introduction and references expanded. Published versio