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.

Compatibility of medications with 3-in-1 parenteral nutrition admixtures.

BACKGROUND: The absence of drug compatibility information with 3-in-1 parenteral nutrition admixtures has been problematic. The purpose of this project was to evaluate the physical compatibility of 106 selected drugs during simulated Y-site injection into nine different 3-in-1 parenteral nutrition admixture formulations. METHODS: Four-milliliter samples of each of the representative 3-in-1 parenteral nutrition admixture formulations were combined in a 1:1 ratio with 4-mL samples of each of 106 drugs, including supportive care drugs, anti-infectives, and antineoplastic drugs. Six replicate samples of each combination were prepared. Two samples were evaluated initially after mixing, two more after 1 hour, and the last two after 4 hours at 23 degrees C. At each test interval, the samples were subjected to centrifugation, causing the fat to rise to the top. The top fat layer and most of the aqueous phase were removed, and the remaining liquid was diluted with about 7 mL of particle-free, high-performance liquid chromatography-grade water to facilitate observation of any particulates that might have formed. Visual examinations were performed in normal diffuse fluorescent laboratory light and under high-intensity, monodirectional light. RESULTS: Most of the drugs tested were physically compatible with the 3-in-1 parenteral nutrition admixtures for 4 hours at 23 degrees C. However, 23 drugs exhibited various incompatibilities with one or more of the parenteral nutrition admixtures. Six drugs resulted in the formation of precipitate with some or all of the admixtures. Seventeen drugs caused disruption of the emulsion, usually with oiling out. CONCLUSIONS: Most of the test drugs were physically compatible with the nine representative 3-in-1 parenteral nutrition admixtures. However, the 23 drugs that resulted in incompatibilities should not be administered simultaneously with the incompatible parenteral nutrition admixtures via a Y injection site.

Compatibility of parenteral nutrient solutions with selected drugs during simulated Y-site administration.

The compatibility of 102 drugs with parenteral nutrient (PN) solutions during simulated Y-site administration was studied. Five milliliters of each of four representative PN solutions was combined in duplicate in a 1:1 ratio with 5-mL samples of solutions of 102 drugs in 5% dextrose injection or 0.9% sodium chloride injection. Visual examinations were performed in fluorescent laboratory light and under high-intensity monodirectional light, and turbidity was measured. Particle sizing and counting were performed for selected solutions. All evaluations were performed at intervals up to four hours; storage was at 23 degrees C. Most of the drugs tested were compatible with the PN solutions. However, 20 drugs exhibited various incompatibilities with one or more of the PN solutions. During simulated Y-site administration, four PN solutions were compatible with 82 of 102 drugs for four hours at 23 degrees C. Twenty drugs were incompatible with one or more of the PN solutions.