Structure activity relationship towards design of cryptosporidium specific thymidylate synthase inhibitors
Explore the source record for details and available documents.
99 GENERAL AND MISCELLANEOUS↗
SEARCH · Search NASA
Results for “Structural Design”
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.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Structure-Based Design of Novel Pyrimido[4,5-c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity
Dihydropteroate synthase (DHPS) is the validated drug target for sulfonamide antimicrobial therapy. However, due to widespread drug resistance and poor tolerance, the use of sulfonamide antibiotics is now limited. The pterin binding pocket in DHPS is highly conserved and is distinct from the sulfonamide binding site. It therefore represents an attractive alternative target for the design of novel antibacterial agents. We previously carried out the structural characterization of a known pyridazine inhibitor in the Bacillus anthracis DHPS pterin site and identified a number of unfavorable interactions that appear to compromise binding. With this structural information, a series of 4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazines were designed to improve binding affinity. Most importantly, the N-methyl ring substitution was removed to improve binding within the pterin pocket, and the length of the side chain carboxylic acid was optimized to fully engage the pyrophosphate binding site. These inhibitors were synthesized and evaluated by an enzyme activity assay, X-ray crystallography, isothermal calorimetry, and surface plasmon resonance to obtain a comprehensive understanding of the binding interactions from structural, kinetic, and thermodynamic perspectives. This study clearly demonstrates that compounds lacking the N-methyl substitution exhibit increased inhibition of DHPS, but the beneficial effects of optimizing the side chain length are less apparent.
59 BASIC BIOLOGICAL SCIENCES↗
Challenges and Optimization of Mu2e Proton Target Design with Radiative Cooling
Mu2e, the Muon-to-Electron Conversion Experiment, aims to identify physics beyond the Standard Model, namely, the conversion of muons to electrons without the emission of neutrinos. The muons are produced from pions generated in a production target when it is hit by an 8 GeV proton beam from the Fermilab Booster/Main Injector. The proton target design space is strongly constrained by a one-year operating lifetime and the need for radiative cooling in a vacuum environment. Uncertainties in the lifetime of the existing baseline design – a monolithic, segmented tungsten target – are large, particularly due to unknown impacts of radiation damage at the very high proton fluences expected in the experiment. We have begun evaluation of a new design utilizing Inconel 718 over the WL10 used in the existing target design. As a result, the structural design of the target has evolved significantly. This evolution focuses on lowering the target temperature, minimizing obstruction to muons, increasing structural stability, maximizing fatigue lifetime, simplifying the fabrication process, and more. The thermal management, structural stability and fatigue lifetime are emphasized here. These optimizations have led to a promising new target design for the Mu2e experiment.
Liu, Z. [Fermilab]↗
RCSB Protein Data Bank resources for structure-facilitated design of mRNA vaccines for existing and emerging viral pathogens
Not Available
59 BASIC BIOLOGICAL SCIENCES↗
Structure-based design of potent HIV-1 protease inhibitors with modified P1-biphenyl ligands: Synthesis, biological evaluation, and enzyme–inhibitor X-ray structural studies
Abstract not provided
59 BASIC BIOLOGICAL SCIENCES↗
Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase
Selective inhibitors of protein lysine methyltransferases, including SET domain-containing protein 8 (SETD8), are highly desired, as only a fraction of these enzymes are associated with high-quality inhibitors. From our previously discovered SETD8 inhibitor, we developed a more potent analog and solved a cocrystal structure, which is the first crystal structure of SETD8 in complex with a small-molecule inhibitor. This cocrystal structure allowed the design of a covalent inhibitor of SETD8 (MS453), which specifically modifies a cysteine residue near the inhibitor binding site, has an IC 50 value of 804 nM, reacts with SETD8 with near-quantitative yield, and is selective for SETD8 against 28 other methyltransferases. We also solved the crystal structure of the covalent inhibitor in complex with SETD8. In conclusiont, this work provides atomic-level perspective on the inhibition of SETD8 by small molecules and will help identify high-quality chemical probes of SETD8.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Sub-MeV ultra-compact linac for radioactive isotope sources replacement, non-destructive testing, security and medical applications
RadiaBeam Technologies, LLC has developed an inexpensive, hand-portable 180 keV electron accelerator to replace 57 Co radionuclide sources in Cascade Header Enrichment Monitor detectors. We used two innovative technologies in our design: a Ku-band (1 cm wavelength) magnetron, and a split accelerating structure design to reduce manufacturing costs. In this paper, we will discuss the accelerator, including X-ray convertor and accelerating structure design. The results of RF measurements of a Ku-band split structure prototype will also be reviewed. Other applications of Ku-band linacs include compact backscatter and transmission X-ray security inspection systems, as well as computed tomography (CT) systems for luggage and parcel screening. The main requirement for luggage inspection systems is that the X-ray source must be extremely compact. Further, the required energies should cover the range from 180 keV to 1 MeV. In this paper, we will discuss the linac’s energy scalability and other modifications that will enable our technology to address these applications.
46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
A deep learning and finite element approach for exploration of inverse structure–property designs of lightweight hybrid composites
Hybrid composites have important applications, such as high-performance and lightweight materials in aerospace and automotive industries. Hybrid composites utilize the synergy of diverse fillers to achieve desired material properties, but usually have more complicated microstructures. While topology optimization can optimize a particular property, designing hybrid composites for customized mechanical performances, e.g. full-range stress–strain curve, remains challenging. Here, a computational framework that integrated finite element analysis (FEA) and artificial intelligence (AI) methods of Conditional Generative Adversarial Networks (cGAN) deep learning and transfer learning was developed to establish inverse structure–property relationships and design tailor-made hybrid composites. Based on FEA-generated datasets of hybrid fiber-particle–matrix microstructures and their corresponding full-range stress–strain curves, a cGAN architecture was trained to generate tailored microstructures and establish structure–property relationships. Similarity in microstructural features and well-matched stress–strain curves based on the AI-generated composites were achieved. In conclusion, transfer learning was used to expand the pre-trained model for designing different materials systems.
Hybrid composites↗
Structure-Based Design of Functional Amyloid Materials
We report that amyloid fibers, once exclusively associated with disease, are acquiring utility as a class of biological nanomaterials. We introduce a method that utilizes the atomic structures of amyloid peptides, to design materials with versatile applications. As a model application, we designed amyloid fibers capable of capturing carbon dioxide from flue gas, to address the global problem of excess anthropogenic carbon dioxide. By measuring dynamic separation of carbon dioxide from nitrogen, we show that fibers with designed amino acid sequences double the carbon dioxide binding capacity of the previously reported fiber formed by VQIVYK from Tau protein. In a second application, we designed fibers that facilitate retroviral gene transfer. Finally, by measuring lentiviral transduction, we show that designed fibers exceed the efficiency of polybrene, a commonly used enhancer of transduction. The same procedures can be adapted to the design of countless other amyloid materials with a variety of properties and uses.
60 APPLIED LIFE SCIENCES↗
GeneratorSE: A Sizing Tool for Variable-Speed Wind Turbine Generators
This report documents a set of analytical models employed by the optimization algorithms within the GeneratorSE framework. The initial values and boundary conditions employed for the generation of the various designs and initial estimates for basic design dimensions, masses, and efficiency for the four different models of generators are presented and compared with empirical data collected from previous studies and some existing commercial turbines. These models include designs applicable for variable-speed, high-torque application featuring direct-drive synchronous generators and low-torque application featuring induction generators. In all of the four models presented, the main focus of optimization is electromagnetic design with the exception of permanent-magnet and wire-wound synchronous generators, wherein the structural design is also optimized. Thermal design is accommodated in GeneratorSE as a secondary attribute by limiting the winding current densities to acceptable limits. A preliminary validation of electromagnetic design was carried out by comparing the optimized magnetic loading against those predicted by numerical simulation in FEMM4.2, a finite-element software for analyzing electromagnetic and thermal physics problems for electrical machines. For direct-drive synchronous generators, the analytical models for the structural design are validated by static structural analysis in ANSYS.
17 WIND ENERGY↗
The influence of molecular design on structure–property relationships of a supramolecular polymer prodrug
Supramolecular self-assemblies of hydrophilic macromolecules functionalized with hydrophobic, structure-directing components have long been used for drug delivery. In these systems, loading of poorly soluble compounds is typically achieved through physical encapsulation during or after formation of the supramolecular assembly, resulting in low encapsulation efficiencies and limited control over release kinetics, which are predominately governed by diffusion and carrier degradation. To overcome these limitations, amphiphilic prodrugs that leverage a hydrophobic drug as both the therapeutic and structure-directing component can be used to create supramolecular materials with higher loading and controlled-release kinetics using biodegradable or enzymatically cleavable linkers. Here, we report the design, synthesis, and characterization of a library of supramolecular polymer prodrugs based on poly(ethylene glycol) (PEG) and the proregenerative drug 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (DPCA). Structure–property relationships were elucidated through experimental characterization of prodrug behavior in both the wet and dry states using scattering techniques and electron microscopy and corroborated by coarse-grained modeling. Molecular architecture and the hydrophobic-to-hydrophilic ratio of PEG–DPCA conjugates strongly influenced their physical state in water, ranging from fully soluble to supramolecular spherical assemblies and nanofibers. Molecular design and supramolecular structure, in turn, were shown to dramatically alter hydrolytic and enzymatic release and cellular transport of DPCA. In addition to potentially expanding therapeutic options for DPCA through control of supramolecular assemblies, the design principles elaborated here may inform the development of other supramolecular prodrugs based on hydrophobic small-molecule compounds.
77 NANOSCIENCE AND NANOTECHNOLOGY↗
Designing the Structure of Carbon Fibers for Optimal Mechanical Properties
Carbon fiber manufacturing follows generic processing steps: formation of thermoplastic fibers, stabilization, and carbonization. The final structures and end properties of the carbon fiber can differ significantly depending on the precursor chemistry and the associated processing sciences. Polyacrylonitrile (PAN) and mesophase pitch are the predominant precursors used in the production of carbon fibers. PAN-based carbon fibers consist of nanocrystalline graphitic domains typically 1.5 5 nm in size surrounded by amorphous carbon; in contrast, pitch-based carbon fibers are 10 50 nm crystallites with the graphitic (002) planes mostly aligned parallel to the fiber axis. It has been seen that the skin core structure of PAN-based carbon fibers plays a significant role in their mechanical properties. Designing a more homogenous carbon fiber microstructure by controlling the starting polymer and process parameters results in a different set of tensile strengths and elastic moduli. In this study the microstructural defect distribution (0.1 200 nm), measured by small-angle X-ray scattering, was shown to be directly related to the tensile strength of the carbon fibers. Here the formation of carbon structures from various polymer precursors is reviewed. Such a comprehensive understanding offers the opportunity to design carbon fiber microstructures with improved properties and to ultimately create new types of carbon fibers from alternative precursors at reduced cost.
Ozcan, Soydan↗
Gamma discrimination in pillar structured thermal neutron detectors
Solid-state thermal neutron detectors are desired to replace {sup 3}He tube based technology for the detection of special nuclear materials. {sup 3}He tubes have some issues with stability, sensitivity to microphonics and very recently, a shortage of {sup 3}He. There are numerous solid-state approaches being investigated that utilize various architectures and material combinations. By using the combination of high-aspect-ratio silicon PIN pillars, which are 2 {micro}m wide with a 2 {micro}m separation, arranged in a square matrix, and surrounded by {sup 10}B, the neutron converter material, a high efficiency thermal neutron detector is possible. Besides intrinsic neutron detection efficiency, neutron to gamma discrimination is an important figure of merit for unambiguous signal identification. In this work, theoretical calculations and experimental measurements are conducted to determine the effect of structure design of pillar structured thermal neutron detectors including: intrinsic layer thickness, pillar height, substrate doping and incident gamma energy on neutron to gamma discrimination.
72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
Flutter behavior of highly flexible blades for two- and three-bladed wind turbines
Abstract. With the progression of novel design, material, and manufacturing technologies, the wind energy industry has successfully produced larger and larger wind turbine rotor blades while driving down the levelized cost of energy (LCOE). Though the benefits of larger turbine blades are appealing, larger blades are prone to aeroelastic instabilities due to their long, slender, highly flexible nature, and this effect is accentuated as rotors further grow in size. In addition to the trend of larger rotors, non-traditional rotor concepts are emerging including two-bladed rotors and downwind configurations. In this work, we introduce a comprehensive evaluation of flutter behavior including classical flutter, edgewise vibration, and flutter mode characteristics for two-bladed, downwind rotors. Flutter speed trends and characteristics for a series of both two- and three-bladed rotors are analyzed and compared in order to illustrate the flutter behavior of two-bladed rotors relative to more well-known flutter characteristics of three-bladed rotors. In addition, we examine the important problem of blade design to mitigate flutter and present a solution to mitigate flutter in the structural design process. A study is carried out evaluating the effect of leading edge and trailing edge reinforcement on flutter speed and hence demonstrates the ability to increase the flutter speed and satisfy structural design requirements (such as fatigue) while maintaining or even reducing blade mass.
Chetan, Mayank (ORCID:0000000241978801)↗
Structure-Based Design of a Novel Series of Potent, Selective Inhibitors of the Class I Phosphatidylinositol 3-Kinases
A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.
59 BASIC BIOLOGICAL SCIENCES↗
Tandem Catalysis for CO 2 Hydrogenation to C 2 –C 4 Hydrocarbons
Conversion of carbon dioxide to C 2 -C 4 hydrocarbons is a major pursuit in clean energy research. Despite tremendous efforts, the lack of well-defined catalysts in which the spatial arrangement of interfaces is precisely controlled hinders the development of more efficient catalysts and in-depth understanding of reaction mechanisms. Herein, we utilized the strategy of tandem catalysis to develop a well-defined nanostructured catalyst CeO 2 -Pt@mSiO2-Co for converting CO 2 to C 2 -C 4 hydrocarbons using two metal-oxide interfaces. C 2 -C 4 hydrocarbons are found to be produced with high (60%) selectivity, which is speculated to be the result of the two-step tandem process uniquely allowed by this catalyst. Namely, the Pt/CeO 2 interface converts CO 2 and H 2 to CO, and on the neighboring Co/mSiO 2 interface yields C 2 -C 4 hydrocarbons through a subsequent Fischer-Tropsch process. In addition, the catalysts show no obvious deactivation over 40 h. The successful production of C 2 -C 4 hydrocarbons via a tandem process on a rationally designed, structurally well-defined catalyst demonstrates the power of sophisticated structure control in designing nanostructured catalysts for multiple-step chemical conversions.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Molecular design for growth of supramolecular membranes with hierarchical structure
Membranes with hierarchical structure exist in biological systems, and bio-inspired building blocks have been used to grow synthetic analogues in the laboratory through self-assembly. The formation of these synthetic membranes is initiated at the interface of two aqueous solutions, one containing cationic peptide amphiphiles (PA) and the other containing the anionic biopolymer hyaluronic acid (HA). The membrane growth process starts within milliseconds of interface formation and continues over much longer timescales to generate robust membranes with supramolecular PA–HA nanofibers oriented orthogonal to the interface. Computer simulation indicates that formation of these hierarchically structured membranes requires strong interactions between molecular components at early time points in order to generate a diffusion barrier between both solutions. Experimental studies using structurally designed PAs confirm simulation results by showing that only PAs with high ζ potential are able to yield hierarchically structured membranes. Furthermore, the chemical structure of such PAs must incorporate residues that form β-sheets, which facilitates self-assembly of long nanofibers. In contrast, PAs that form low aspect ratio nanostructures interact weakly with HA and yield membranes that exhibit non-fibrous fingering protrusions. Furthermore, experimental results show that increasing HA molecular weight decreases the growth rate of orthogonal nanofibers. Overall, this result is supported by simulation results suggesting that the thickness of the interfacial contact layer generated immediately after initiation of self-assembly increases with polymer molecular weight.
36 MATERIALS SCIENCE↗