Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

In vitro activity of a combination of bacteriophages and antimicrobial plant extracts.

The continuing threat of antimicrobial resistance presents a considerable challenge to researchers to develop novel strategies ensuring that bacterial infections remain treatable. Many plant extracts have been shown to have antibacterial properties and could potentially be combined with other antibacterial agents to create more effective formulations. In this study, the antibacterial activity of three plant extracts and virulent bacteriophages have been assessed as individual components and in combination. When assessed with a modified suspension test, these plant extracts also exhibit antiviral activity at bacterial inhibitory concentrations. Hence, to investigate any potential additive effects between the extracts and virulent phages, the extracts were tested at subantiviral concentrations. Phages alone and in combination with plant extracts significantly reduced (P < 0·05) the bacterial concentration compared to untreated and extract treated controls up to 6 h (2-3log10 ), but this reduction did not extend to 24 h. In most cases, the phage and extract combinations did not significantly reduce bacterial content compared to phages alone. Additionally, there was little impact on the ability of the phages to reproduce within their bacterial hosts. To our knowledge, this study represents the first of its kind, in which antimicrobial plant extracts have been combined with virulent phages and has highlighted the necessity for plant extracts to be functionally characterized prior to the design of combinatorial therapies. Significance and Impact of Study This preliminary study provides insights into the potential combination of bacteriophages and antimicrobial plant bulk extracts to target bacterial pathogens. It is to our knowledge the first time in which virulent bacteriophages have been combined with antimicrobial plant extracts.

Bacteriophages and bacteriophage-derived endolysins as potential therapeutics to combat Gram-positive spore forming bacteria.

Since their discovery in 1915, bacteriophages have been routinely used within Eastern Europe to treat a variety of bacterial infections. Although initially ignored by the West due to the success of antibiotics, increasing levels and diversity of antibiotic resistance is driving a renaissance for bacteriophage-derived therapy, which is in part due to the highly specific nature of bacteriophages as well as their relative abundance. This review focuses on the bacteriophages and derived lysins of relevant Gram-positive spore formers within the Bacillus cereus group and Clostridium genus that could have applications within the medical, food and environmental sectors.