The Influence of 150-Cavity Binders on the Dynamics of Influenza A Neuraminidases as Revealed by Molecular Dynamics Simulations and Combined Clustering

Neuraminidase inhibitors are the main pharmaceutical agents employed for treatments of influenza infections. The neuraminidase structures typically exhibit a 150-cavity, an exposed pocket that is adjacent to the catalytic site. This site offers promising additional contact points for improving potency of existing pharmaceuticals, as well as generating entirely new candidate inhibitors. Several inhibitors based on known compounds and designed to interact with 150-cavity residues have been reported. However, the dynamics of any of these inhibitors remains unstudied and their viability remains unknown. This work reports the outcome of long-term, all-atom molecular dynamics simulations of four such inhibitors, along with three standard inhibitors for comparison. Each is studied in complex with four representative neuraminidase structures, which are also simulated in the absence of ligands for comparison, resulting in a total simulation time of 9.6µs. Our results demonstrate that standard inhibitors characteristically reduce the mobility of these dynamic proteins, while the 150-binders do not, instead giving rise to many unique conformations. We further describe an improved RMSD-based clustering technique that isolates these conformations – the structures of which are provided to facilitate future molecular docking studies – and reveals their interdependence. We find that this approach confers many advantages over previously described techniques, and the implications for rational drug design are discussed

To 'enable our legal product to compete effectively with the transit market' : British American Tobacco's strategies in Thailand following the 1990 GATT dispute

The opening of the Thai tobacco market, following action brought by the US Trade Representative under the General Agreement on Tariffs and Trade, is seen as a key case study of the tensions between trade and health policy. Interpretations of the dispute cast it, either as an example of how trade agreements undermine national policy-making, or how governments can adopt effective public health protections compliant with international trade rules. As a UK-based company, British American Tobacco has been regarded as peripheral to this dispute. This paper argues that its close monitoring of the illegal trade during this period, the role of smuggling in the company's global business strategy, and its management of the relative supply and pricing of legal and illegal products after market opening provide a fuller understanding of the interests and roles of transnational tobacco companies and the government in this dispute. The findings have important policy implications, notably the role of effective governance in countries facing pressure to open their tobacco sectors, need to better understand corporate-level activities within an increasingly globalised tobacco industry, and need to address the intertwined legal and illegal trade in implementing the WHO Framework Convention on Tobacco Control Protocol to Eliminate Illicit Trade in Tobacco Products.15 page(s

Mapping SARS-CoV-2 antigenic relationships and serological responses

Vaccination has greatly reduced the disease burden of SARS-CoV-2. However, since late 2020, variants have emerged that are able to escape immunity from vaccination and previous infections, including B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron and its descendants). In combination with vaccination, infections with different variants form the basis of current population immunity against SARS-CoV-2

N2-1 alternate enzyme poses.

<p>Shown are the C1, C3, C8 of N2 with L1 of <b>3</b>. The color scheme is identical to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059873#pone-0059873-g005" target="_blank">Figure 5</a>.</p

Simultaneous 150-loop closure and ligand sidechain ejection for N8_open-6.

<p>Shown is C1 and C3 of N8_open with L1 and L2 of <b>6</b>. The color scheme is identical to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059873#pone-0059873-g005" target="_blank">Figure 5</a>.</p