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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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165 records · Page 10
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

Discrete Open-Shell Tris(bipyridinium radical cationic) Inclusion Complexes in the Solid State

In the solid state the properties of organic radicals depend heavily on radical-radical interactions that are influenced by the superstructure of the crystalline phase. Here, we report the synthesis and characterization of a substituted tetracationic cyclophane, cyclobis(paraquat-p-1,4- dimethoxyphenylene), and outline how its bisradical dicationic redox state associates with the methyl viologen radical cation (MV •+ ) to give a trisradical tricationic inclusion complex. The (super)structures of the reduced cyclophane and this 1:1 complex in the solid-state deviate from the analogous (super)structures observed for the reduced state of cyclobis(paraquat-p-phenylene) and that of its trisradical tricationic complex. Titration experiments with a range of guests reveal that the methoxy substituents on the para-xylenyl do not influence significantly of the binding affinity of the cyclophane for small neutral guests, whereas the affinity decreases by an order of magnitude for larger radical cationic guests such as MV •+ . X-Ray diffraction reveals that the solid- state structures of the tricationic trisradical complexes to be a discrete entity with weak intermolecular orbital overlap between the neighboring complexes. Transient nutation EPR experiment and DFT calculations confirm that the complex has a doublet spin configuration in the ground state as a result of the strong orbital overlap within the complex, while the quartet-state spin configuration is higher in energy and so is inaccessible at ambient temperature. The superconducting quantum interference device (SQUID) measurement reveals that trisradical tricationic complexes interact antiferromagnetically (J/k = - 2.33 K) and form a 1D Heisenberg antiferromagnetic chain along the a-axis in the crystal. Furthermore, these results offer new insights into the design and synthesis of organic magnetic materials based on host-guest inclusion complexes.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

Mechanistic Duality of Bacterial Efflux Substrates and Inhibitors: Example of Simple Substituted Cinnamoyl and Naphthyl Amides

Antibiotic resistance poses an immediate and growing threat to human health. Multidrug efflux pumps are promising targets for overcoming antibiotic resistance with small-molecule therapeutics. Previously, we identified a diaminoquinoline acrylamide, NSC-33353, as a potent inhibitor of the AcrAB–TolC efflux pump in Escherichia coli. This inhibitor potentiates the antibacterial activities of novobiocin and erythromycin upon binding to the membrane fusion protein AcrA. It is also a substrate for efflux and lacks appreciable intrinsic antibacterial activity of its own in wild-type cells. Here, we have modified the substituents of the cinnamoyl group of NSC-33353, giving rise to analogs that retain the ability to inhibit efflux, lost the features of the efflux substrates, and gained antibacterial activity in wild-type cells. The replacement of the cinnamoyl group with naphthyl isosteres generated compounds that lack antibacterial activity but are both excellent efflux pump inhibitors and substrates. Surprisingly, these inhibitors potentiate the antibacterial activity of novobiocin but not erythromycin. Surface plasmon resonance experiments and molecular docking suggest that the replacement of the cinnamoyl group with naphthyl shifts the affinity of the compounds away from AcrA to the AcrB transporter, making them better efflux substrates and changing their mechanism of inhibition. These results provide new insights into the duality of efflux substrate/inhibitor features in chemical scaffolds that will facilitate the development of new efflux pump inhibitors.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

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

In this work, 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.

60 APPLIED LIFE SCIENCES↗