Search NASA⌕ Search

SEARCH · Search NASA

Results for “DRUG”

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.

At least 235 records · Page 13
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Machine Learning Discrimination and Ultrasensitive Detection of Fentanyl Using Gold Nanoparticle-Decorated Carbon Nanotube-Based Field-Effect Transistor Sensors

The opioid overdose crisis is a global health challenge. Fentanyl, an exceedingly potent synthetic opioid, has emerged as a leading contributor to the surge in opioid-related overdose deaths. The surge in overdose fatalities, particularly due to illicitly manufactured fentanyl and its contamination of street drugs, emphasizes the urgency for drug-testing technologies that can quickly and accurately identify fentanyl from other drugs and quantify trace amounts of fentanyl. In this paper, gold nanoparticle (AuNP)-decorated single-walled carbon nanotube (SWCNT)-based field-effect transistors (FETs) are utilized for machine learning-assisted identification of fentanyl from codeine, hydrocodone, and morphine. The unique sensing performance of fentanyl led to use machine learning approaches for accurate identification of fentanyl. Employing linear discriminant analysis (LDA) with a leave-one-out cross-validation approach, a validation accuracy of 91.2% is achieved. Meanwhile, density functional theory (DFT) calculations reveal the factors that contributed to the enhanced sensitivity of the Au-SWCNT FET sensor toward fentanyl as well as the underlying sensing mechanism. Finally, fentanyl antibodies are introduced to the Au-SWCNT FET sensor as specific receptors, expanding the linear range of the sensor in the lower concentration range, and enabling ultrasensitive detection of fentanyl with a limit of detection at 10.8 fg mL –1 .

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

Exploring the Effects of Intersubunit Interface Mutations on Virus-Like Particle Structure and Stability

Virus-like particles (VLPs) from bacteriophage MS2 provide a platform to study protein self-assembly and create engineered systems for drug delivery. Here, we aim to understand the impact of intersubunit interface mutations on the local and global structure and function of MS2-based VLPs. In previous work, our lab identified locally supercharged double mutants [T71K/G73R] that concentrate positive charge at capsid pores, enhancing uptake into mammalian cells. To study the effects of particle size on cellular internalization, we combined these double mutants with a single point mutation [S37P] that was previously reported to switch particle geometry from T = 3 to T = 1 icosahedral symmetry. These new variants retained their enhanced cellular uptake activity and could deliver small-molecule drugs with efficacy levels similar to our first-generation capsids. Surprisingly, these engineered triple mutants exhibit increased thermostability and unexpected geometry, producing T = 3 particles instead of the anticipated T = 1 assemblies. Transmission electron microscopy revealed various capsid assembly states, including wild-type (T = 3), T = 1, and rod-like particles, that could be accessed using different combinations of these point mutations. Molecular dynamics experiments recapitulated the structural rationale in silico for the single point mutation [S37P] forming a T = 1 virus-like particle and showed that this assembly state was not favored when combined with mutations that favor rod-like architectures. Through this work, we investigated how interdimer interface dynamics influence VLP size and morphology and how these properties affect particle function in applications such as drug delivery.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

RTx-303, an Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates PARP Inhibitors in BRCA Mutant Tumors

Abstract DNA polymerase θ (Polθ) is a polymerase-helicase fusion protein that is synthetically lethal with homologous recombination (HR) factors, such as BRCA1/2, and confers resistance to PARP inhibitors (PARPi) and other genotoxic cancer therapies. Previously developed Polθ polymerase (Polθ-pol) inhibitors (Polθi) exhibited limited pharmacological activity and metabolic stability, warranting the development of a Polθi with improved drug-like properties. Here, we developed RTx-303, a selective allosteric small-molecule Polθ-pol inhibitor that exhibits 5.1 nM IC50, 88% oral bioavailability, and a prolonged half-life along with its equipotent metabolite. X-ray crystallography highlights the development of a solvent-exposed side-chain that is essential for the optimal drug-like properties of RTx-303. Notably, RTx-303 exhibits significantly higher cellular potency than previously developed Polθ-pol inhibitors and strongly potentiates PARPi in BRCA1/2 mutant cells and patient-derived xenograft models. The superior potency, robust pharmacological activity, and high tolerability of RTx-303 warrant further development as a Polθ-pol inhibitor drug candidate.

Chandramouly, Gurushankar [Thomas Jefferson Univer↗
DOE OSTI2025

Optimization of Species-Selective Reversible Proteasome Inhibitors for the Treatment of Malaria

Abstract Malaria remains a critical global health challenge, with increasing resistance to frontline therapies necessitating novel drug targets. The proteasome has emerged as a promising target for antimalarial drug discovery. This study describes efforts to optimize a series of species-selective reversible inhibitors targeting the Plasmodium falciparum 20S proteasome. Starting from the carboxypiperidine scaffold identified through a high-throughput viability screen, we conducted iterative structure–activity relationship studies, leading to the development of highly potent and selective inhibitors with good oral bioavailability. Lead compounds demonstrated nanomolar potency against P. falciparum blood-stage parasites and selective inhibition of the parasite proteasome over the human counterpart. Cryo-EM structural studies confirmed binding at the β5 subunit, while in vivo pharmacokinetic studies identified promising candidates for further development. These findings support proteasome inhibition as a viable strategy for novel antimalarial drug development.

Gahalawat, Suraksha [UT Southwestern Medical Cente↗
DOE OSTI2026

A Prodrug Strategy to Conditionally Trap Therapeutic Payloads for Improved Tumor Retention

Altered extracellular proteolysis has been exploited to selectively activate therapeutics in diseases such as cancer; however, once activated, extracellular drugs can diffuse away, limiting efficacy. We address this challenge by coupling proteolytic activation with membrane tethering to retain drugs within diseased tissue. To accomplish this, we developed “restricted interaction peptides” (RIPs), a delivery platform that leverages elevated proteolytic activity to activate membrane-interacting peptides, localizing cargos near the site of proteolysis. We demonstrate that RIPs can deliver diverse therapeutic cargos, including cytotoxins and radioisotopes. As proof of concept, we engineered “FRIP,” a RIP designed for cleavage by fibroblast activation protein (FAP), an endoprotease upregulated in solid tumors and fibrosis. Efficient P4–P4’ substrate sequences were identified and incorporated into FRIPs. Cell-based studies showed that, upon activation, the peptide adhered to membranes rapidly internalized and successfully delivered therapeutic cargos. Consistent with this, FRIPs delivering MMAE inhibited proliferation in an FAP-dependent manner. Imaging studies confirmed tumor targeting with minimal uptake in normal tissues. Finally, FRIPs delivering MMAE or Cu-67 exhibited potent antitumor effects. These findings establish membrane tethering as a strategy to enhance drug retention.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Comparing Liquid Vortex Capture & the Rapid Droplet Sampling Interface for Single Cell Mass Spectrometry

High-throughput single-cell mass spectrometry is a rapidly evolving field that requires innovative sampling and ionization techniques to balance speed, sensitivity, and reliability for metabolomic and lipidomic analyses. This study provides a comparative analysis of two cutting-edge ionization platforms for single-cell analysis: Liquid Vortex Capture (LVC) and Rapid Droplet Sampling Interface (RDSI). The performance was benchmarked by testing pharmaceuticals, EquiSPLASH, and single-cell experiments. RDSI demonstrated up to 100-fold improvements in sensitivity for drugs and lipids such as propranolol, amiodarone, atorvastatin, and phosphocholines in water and phosphate-buffered solutions. This was attributed to its low-flow rate operation (3 μL/min) and reduced dilution. Conversely, LVC excelled in handling higher liquid volumes with greater reproducibility due to its higher solvent flow rate (200 μL/min), enabling increased dilution, solubility, and cleaning. Single-cell uptake of atorvastatin incubated for 10 min, or amiodarone incubated for 24 h in HepG2 cells, similarly revealed up to 85-fold enhancement in sensitivity by RDSI for drugs and lipids. These findings highlight the potential of RDSI for enhancing sensitivity in single-cell drug monitoring and lipidomics.

Cahill, John [ORNL] (ORCID:0000000298664010)↗
DOE OSTI2024

Identifying Bayesian optimal experiments for uncertain biochemical pathway models

Abstract Pharmacodynamic (PD) models are mathematical models of cellular reaction networks that include drug mechanisms of action. These models are useful for studying predictive therapeutic outcomes of novel drug therapies in silico. However, PD models are known to possess significant uncertainty with respect to constituent parameter data, leading to uncertainty in the model predictions. Furthermore, experimental data to calibrate these models is often limited or unavailable for novel pathways. In this study, we present a Bayesian optimal experimental design approach for improving PD model prediction accuracy. We then apply our method using simulated experimental data to account for uncertainty in hypothetical laboratory measurements. This leads to a probabilistic prediction of drug performance and a quantitative measure of which prospective laboratory experiment will optimally reduce prediction uncertainty in the PD model. The methods proposed here provide a way forward for uncertainty quantification and guided experimental design for models of novel biological pathways.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2024

Peptide-mimetic treatment of Pseudomonas aeruginosa in a mouse model of respiratory infection

The rise of drug resistance has become a global crisis, with >1 million deaths due to resistant bacterial infections each year. Pseudomonas aeruginosa, in particular, remains a serious problem with limited solutions due to complex resistance mechanisms that now lead to more than 32,000 multidrug-resistant (MDR) infections and over 2000 deaths in the U.S. annually. While the emergence of resistant bacteria has become ominously common, identification of useful new drug classes has been limited over the past over 40 years. We found that a potential novel therapeutic, the peptide-mimetic TM5, is effective at killing P. aeruginosa and displays sufficiently low toxicity in mammalian cells to allow for use in treatment of infections. Interestingly, TM5 kills P. aeruginosa more rapidly than traditional antibiotics, within 30–60 min in vitro, and is effective against a range of clinical isolates, including extensively drug resistant strains. In vivo, TM5 significantly reduced bacterial load in the lungs within 24 h compared to untreated mice and demonstrated few adverse effects. Taken together, these observations suggest that TM5 shows promise as an alternative therapy for MDR P. aeruginosa respiratory infections.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel K Ca 3.1

The 1,4-dihydropyridines, drugs with well-established bioavailability and toxicity profiles, have proven efficacy in treating human hypertension, peripheral vascular disorders, and coronary artery disease. Every 1,4-dihydropyridine in clinical use blocks L-type voltage-gated calcium channels. We now report our development, using selective optimization of a side activity (SOSA), of a class of 1,4-dihydropyridines that selectively and potently inhibit the intermediate-conductance calcium-activated K + channel K Ca 3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked K Ca 3.1 with an IC 50 of 6 nM and exhibited exquisite selectivity over calcium channels and a panel of >100 additional molecular targets. Using high-resolution structure determination by cryogenic electron microscopy together with mutagenesis and electrophysiology, we delineated the drug binding pocket for DHP-103 within the water-filled central cavity of the K Ca 3.1 channel pore, where bound drug directly impedes ion permeation. DHP-103 inhibited gain-of-function mutant K Ca 3.1 channels that cause hereditary xerocytosis, suggesting its potential use as a therapeutic for this hemolytic anemia. In a rat model of acute ischemic stroke, the second leading cause of death worldwide, DHP-103 administered 12 h postischemic insult in proof-of-concept studies reduced infarct volume, improved balance beam performance (measure of proprioception) and decreased numbers of activated microglia in infarcted areas. K Ca 3.1-selective 1,4-dihydropyridines hold promise for the many diseases for which K Ca 3.1 has been experimentally confirmed as a therapeutic target.

Ong, Seow Theng [Lee Kong Chian School of Medicine↗
DOE OSTI2025

Oxidative stress is a shared characteristic of ME/CFS and Long COVID

Over 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition marked by fatigue, post-exertional malaise, and other symptoms resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). With no clinically approved treatments or reliable diagnostic markers, there is an urgent need to define the molecular underpinnings of these conditions. By studying bioenergetic characteristics of peripheral blood lymphocytes in 25 healthy controls, 27 ME/CFS, and 20 LC donors, we find both ME/CFS and LC donors exhibit signs of elevated oxidative stress, especially in the memory subset. Using a combination of flow cytometry, RNA-seq, mass spectrometry, and systems chemistry analysis, we observed aberrations in reactive oxygen species (ROS) clearance pathways including elevated glutathione levels, decreases in mitochondrial superoxide dismutase protein levels, and glutathione peroxidase 4–mediated lipid oxidative damage. Strikingly, these redox pathways changes show sex-specific trends. While ME/CFS females exhibit higher total ROS and mitochondrial calcium levels, males have normal ROS levels, with pronounced mitochondrial lipid oxidative damage. In females, these higher ROS levels correlate with T cell hyperproliferation, consistent with the known role of elevated ROS in initiating proliferation. This hyperproliferation can be attenuated by metformin, suggesting this Food and Drug Administration (FDA)-approved drug as a possible treatment, as also suggested by a recent clinical study of LC patients. Moreover, these results suggest a shared mechanistic basis for the systemic phenotypes of ME/CFS and LC, which can be detected by quantitative blood cell measurements, and that effective, patient-tailored drugs might be discovered using standard lymphocyte stimulation assays.

ME/CFS↗
DOE OSTI2024

Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy

T-cell engaging (TCE) bispecific antibodies are potent drugs that trigger the immune system to eliminate cancer cells, but administration can be accompanied by toxic side effects that limit dosing. TCEs function by binding to cell surface receptors on T cells, frequently CD3, with one arm of the bispecific antibody while the other arm binds to cell surface antigens on cancer cells. On-target, off-tumor toxicity can arise when the target antigen is also present on healthy cells. The toxicity of TCEs may be ameliorated through the use of pro-drug forms of the TCE, which are not fully functional until recruited to the tumor microenvironment. This can be accomplished by masking the anti-CD3 arm of the TCE with an autoinhibitory motif that is released by tumor-enriched proteases. Here, we solve the crystal structure of the antigen-binding fragment of a novel anti-CD3 antibody, E10, in complex with its epitope from CD3 and use this information to engineer a masked form of the antibody that can activate by the tumor-enriched protease matrix metalloproteinase 2 (MMP-2). We demonstrate with binding experiments and in vitro T-cell activation and killing assays that our designed prodrug TCE is capable of tumor-selective T-cell activity that is dependent upon MMP-2. Furthermore, we demonstrate that a similar masking strategy can be used to create a pro-drug form of the frequently used anti-CD3 antibody SP34. This study showcases an approach to developing immune-modulating therapeutics that prioritizes safety and has the potential to advance cancer immunotherapy treatment strategies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Crystal structure of N-terminally hexahistidine-tagged Onchocerca volvulus macrophage migration inhibitory factor-1

Onchocerca volvulus causes blindness, onchocerciasis, skin infections and devastating neurological diseases such as nodding syndrome. New treatments are needed because the currently used drug, ivermectin, is contraindicated in pregnant women and those co-infected with Loa loa . The Seattle Structural Genomics Center for Infectious Disease (SSGCID) produced, crystallized and determined the apo structure of N-terminally hexahistidine-tagged O. volvulus macrophage migration inhibitory factor-1 (His- Ov MIF-1). Ov MIF-1 is a possible drug target. His- Ov MIF-1 has a unique jellyfish-like structure with a prototypical macrophage migration inhibitory factor (MIF) trimer as the `head' and a unique C-terminal `tail'. Deleting the N-terminal tag reveals an Ov MIF-1 structure with a larger cavity than that observed in human MIF that can be targeted for drug repurposing and discovery. Removal of the tag will be necessary to determine the actual biological oligomer of Ov MIF-1 because size-exclusion chomatographic analysis of His- Ov MIF-1 suggests a monomer, while PISA analysis suggests a hexamer stabilized by the unique C-terminal tails.

Kimble, Amber D. (ORCID:0000000167851596)↗
DOE OSTI2024

Acarbose impairs gut Bacteroides growth by targeting intracellular glucosidases

ABSTRACT Acarbose is a type 2 diabetes medicine that prevents dietary starch breakdown into glucose by inhibiting host amylase and glucosidase enzymes. Numerous gut species in theBacteroidesgenus enzymatically break down starch and change in relative abundance within the gut microbiome in acarbose-treated individuals. To mechanistically explain this observation, we used two model starch-degradingBacteroides,Bacteroides ovatus(Bo), andBacteroides thetaiotaomicron(Bt). Bt growth on starch polysaccharides is severely impaired by acarbose, whereas Bo growth is much less affected by the drug. TheBacteroidesuse a starch utilization system (Sus) to grow on starch. We hypothesized that Bo and Bt Sus enzymes are differentially inhibited by acarbose. Instead, we discovered that although acarbose primarily targets the Sus periplasmic GH97 enzymes in both organisms, the drug affects starch processing at multiple other points. Acarbose competes for transport through the TonB-dependent SusC proteins and binds to the Sus transcriptional regulators. Furthermore, Bo expresses a non-Sus GH97 (BoGH97D) when grown in starch with acarbose. The Bt homolog, BtGH97H, is not expressed in the same conditions, nor can overexpression of BoGH97D complement the Bt growth inhibition in the presence of acarbose. This work informs us about unexpected complexities of Sus function and regulation inBacteroides, including variation between related species. Furthermore, this indicates that the gut microbiome may be a source of variable response to acarbose treatment for diabetes. IMPORTANCE Acarbose is a type 2 diabetes medication that works primarily by stopping starch breakdown into glucose in the small intestine. This is accomplished by the inhibition of host enzymes, leading to better blood sugar control via reduced ability to derive glucose from dietary starches. The drug and undigested starch travel to the large intestine where acarbose interferes with the ability of some bacteria to grow on starch. However, little is known about how gut bacteria interact with acarbose, including microbes that can use starch as a carbon source. Here, we show that two gut species,Bacteroides ovatus(Bo) andBacteroides thetaiotaomicron(Bt), respond differently to acarbose: Bt growth is inhibited by acarbose, while Bo growth is less affected. We reveal a complex set of mechanisms involving differences in starch import and sensing behind the different Bo and Bt responses. This indicates the gut microbiome may be a source of variable response to acarbose treatment for diabetes via complex mechanisms in common gut microbes.

Microbiology↗
DOE OSTI2024

Lipophilic bisphosphonates reduced cyst burden and ameliorated hyperactivity of mice chronically infected with Toxoplasma gondii

ABSTRACT The current treatments for toxoplasmosis are only active against fast-growing tachyzoites, present in acute infections, with little effect on slow-growing bradyzoites within tissue cysts, present in latent chronic infections. The mitochondrion ofToxoplasma gondiiis essential for its survival, and one of the major anti-parasitic drugs, atovaquone, inhibits the mitochondrial electron transport chain at the coenzyme Q:cytochrome c oxidoreductase site. Coenzyme Q (also known as ubiquinone [UQ]) consists of a quinone head and a lipophilic, isoprenoid tail that anchors UQ to membranes. The synthesis of the isoprenoid unit is essential for cell growth and is inhibited by lipophilic bisphosphonates, which inhibit the parasite growth. In this work, we investigated the effect of lipophilic bisphosphonates on the chronic stages ofT. gondii. We discovered that three lipophilic bisphosphonates (BPH-1218, BPH-1236, and BPH-1238), effective for the acute infection, were also effective in controlling the development of chronic stages. We showed effectiveness by testing them againstin vitrocysts andin vivoderived tissue cysts and, most importantly, these compounds reduced the cyst burden in the brains of chronically infected mice. We monitored the activity of infected mice non-invasively and continuously with a novel device termed the CageDot. A decrease in activity accompanied the acute phase, but mice recovered to normal activity and showed signs of hyperactivity when the chronic infection was established. Moreover, treatment with atovaquone or BPH-1218 ameliorated the hyperactivity observed during the chronic infection. IMPORTANCE Treatment for toxoplasmosis is challenged by a lack of effective drugs to eradicate the chronic stages. Most of the drugs currently used are poorly distributed to the central nervous system, and they trigger allergic reactions in a large number of patients. There is a compelling need for safe and effective treatments for toxoplasmosis. Bisphosphonates (BPs) are analogs of inorganic pyrophosphate and are used for the treatment of bone disorders. BPs target the isoprenoid pathway and are effective against several experimental parasitic infections. Some lipophilic BPs can specifically inhibit the mitochondrial activity ofToxoplasma gondiiby interfering with the mechanism by which ubiquinone is inserted into the inner mitochondrial membrane. In this work, we present the effect of three lipophilic BPs againstT. gondiichronic stages. We also present a new strategy for the monitoring of animal activity during disease and treatment that is non-invasive and continuous.

Microbiology↗
DOE OSTI2024

Neutrons in Structural Biology: Challenges and Opportunities (Workshop Report)

Gaining a thorough understanding of biological systems requires building our knowledge about biological processes from the level of atoms and electrons, and up to whole organisms. Such comprehensive knowledge will allow for a predictive understanding of complex biological systems behavior. It will guide us in the design and development of novel therapeutics and vaccines to tackle existing health threats and to prepare for future pandemics, and it will provide information necessary to create new biomaterials and bio-inspired technologies through manipulation of biological macromolecules, their assemblies, single cells and even microorganisms. Reaching these goals will require a synergistic combination of multiple experimental techniques with molecular calculations and predictive simulations, and the design and development of new techniques and capabilities that bridge current knowledge and technology gaps. Neutron scattering provides unique information about the biomacromolecular structure and function and can play a major role in achieving these goals. A workshop was held to engage the scientific community in identifying pressing challenges in biochemistry, structural biology, enzymology and structure-guided drug design not solved with the current neutron scattering technologies or utilizing other structural biology techniques such as X-ray crystallography, NMR, and cryo-EM. The workshop brought together structural biology, biochemistry and computational experts, as well as early career researchers and students, creating a forum for discussing scientific advancement and collaboration. The workshop included a one-day satellite training workshop where graduate students and postdoctoral researchers were educated in the application of neutron crystallography and small-angle scattering in structural biology. Furthermore, the Instrument Scientific Advisory Board (ISAB) for the development of a macromolecular neutron diffractometer at ORNL’s Second Target Station was introduced at the workshop. The major outcome was that neutrons can provide atomic-level understanding of biomacromolecular structure, function and dynamics which is of paramount importance for addressing the identified challenges. Neutron crystallography, in particular, can resolve long-standing biochemical issues regarding enzyme function by delineating the underlying chemistry and can have a major impact on the design of small-molecule therapeutics, especially in combination with molecular computation (quantum chemistry and molecular dynamics simulations) and the emerging artificial intelligence (AI)-assisted drug design technologies. The unique properties of neutrons, including their high sensitivity to hydrogen and their non-destructive nature, make them ideal probes of biological matter. There is a palpable need in the scientific community to expand and enhance the impact of neutron sciences on biology. Neutron crystallography is the only structural biology method capable of determining positions of all hydrogen atoms in proteins, nucleic acids and their complexes at near-physiological temperatures and of unstable species at cryogenic temperatures. Moreover, neutron analysis is non-ionizing, non-destructive and does not perturb the structure or redox chemistry of active site metal centers and clusters in proteins, which can be invaluable for studying radiation-sensitive metalloprotein complexes. Further, neutron energies used in scattering applications are similar to atomic motions, permitting neutron spectroscopies to characterize the dynamics of biomacromolecules on the picosecond to microsecond timescales. The different sensitivities of neutrons to protium (H) and deuterium (D) isotopes of hydrogen allow enhanced visibility of specific parts of biological complexes through isotopic labeling. The impact of neutrons will be most powerful when neutron scattering is combined with complementary experimental techniques that use photons and electrons, and with high-performance computing. The interconnection and mutuality of the experimental and theoretical capabilities will drive discoveries in biological and health sciences to generate more complete picture of complex biological systems. The major limitation in the field of biological neutron crystallography has been signal-to-noise, demanding large samples that are difficult to produce for the majority of biomacromolecules and limiting the applicability of this technique in biological sciences. A neutron crystallography instrument at the Second Target Station will revolutionize biological science with neutrons by engaging a large scientific community of structural biologists, enabling successful neutron diffraction experiments from radically smaller biomacromolecular crystals, resolving unanswered biochemical questions, and meaningfully contributing to rational drug design. The meeting highlighted 10 grand challenges that will be addressed with this advanced capability over the next decade and beyond, and the recommendations required to help address them are given below.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

A goldilocks computational protocol for inhibitor discovery targeting DNA damage responses including replication-repair functions

While many researchers can design knockdown and knockout methodologies to remove a gene product, this is mainly untrue for new chemical inhibitor designs that empower multifunctional DNA Damage Response (DDR) networks. Here, we present a robust Goldilocks (GL) computational discovery protocol to efficiently innovate inhibitor tools and preclinical drug candidates for cellular and structural biologists without requiring extensive virtual screen (VS) and chemical synthesis expertise. By computationally targeting DDR replication and repair proteins, we exemplify the identification of DDR target sites and compounds to probe cancer biology. Our GL pipeline integrates experimental and predicted structures to efficiently discover leads, allowing early-structure and early-testing (ESET) experiments by many laboratories. By employing an efficient VS protocol to examine protein-protein interfaces (PPIs) and allosteric interactions, we identify ligand binding sites beyond active sites, leveraging in silico advances for molecular docking and modeling to screen PPIs and multiple targets. A diverse 3,174 compound ESET library combines Diamond Light Source DSI-poised, Protein Data Bank fragments, and FDA-approved drugs to span relevant chemotypes and facilitate downstream hit evaluation efficiency for academic laboratories. Two VS per library and multiple ranked ligand binding poses enable target testing for several DDR targets. This GL library and protocol can thus strategically probe multiple DDR network targets and identify readily available compounds for early structural and activity testing to overcome bottlenecks that can limit timely breakthrough drug discoveries. By testing accessible compounds to dissect multi-functional DDRs and suggesting inhibitor mechanisms from initial docking, the GL approach may enable more groups to help accelerate discovery, suggest new sites and compounds for challenging targets including emerging biothreats and advance cancer biology for future precision medicine clinical trials.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1976

Space motion sickness medications - Interference with biomedical parameters

The possibility that drugs administered to Skylab 3 and 4 crewmen for space motion sickness may have interfered with their biomedical evaluation in space is investigated. The mixture of scopolamine and dextroamphetamine produced changes which allow a more valid interpretation of the early biomedical changes ocurring in weightlessness. There is no doubt that the dramatic increase in aldosterone excretion is not attributable to the drug, while the drug could have contributed to the in-flight changes observed in cortisol, epinephrine, heart rate and possibly urine volume.

Vernikos-Danellis, J.↗
NASA NTRS1980

Piracetam and fish orientation during parabolic aircraft flight

Goldfish were flown in parabolic Keplerian trajectories in a KC-135 aircraft to assay both the effectiveness of piracetam as an antimotion sickness drug and the effectiveness of state-dependent training during periods of oscillating gravity levels. Single-frame analyses of infrared films were performed for two classes of responses - role rates in hypogravity or hypogravity orienting responses (LGR) and climbing responses in hypergravity or hypergravity orienting responses (HGR). In Experiment I, preflight training with the vestibular stressor facilitated suppression of LGR by the 10th parabola. An inverse correlation was found between the magnitudes of LGR and HGR. Piracetam was not effective in a state-dependent design, but the drug did significantly increase HGR when injected into trained fish shortly before flight. In Experiment II, injections of saline, piracetam, and modifiers of gamma-aminobutyric acid - aminooxyacetic acid (AOAA) and isonicotinic acid did not modify LGR. AOAA did significantly increase HGR. Thus, the preflight training has a beneficial effect in reducing disorientation in the fish in weightlessness, but the drugs employed were ineffective.

Hoffman, R. B.↗