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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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All sourcesNASA NTRSDOE OSTI
NASA NTRSDate not supplied

Gateway at the Crossroads of Sustainable Lunar Exploration

The Gateway Program has made substantial design and development progress toward delivering a small, human-tended lunar space station purposefully designed to enable sustainable human exploration. The Program integrates partners and providers organizationally and physically as part of the spacecraft. The Power and Propulsion Element (PPE) and the Habitation and Logistics Outpost (HALO) with the European System Providing Refueling, Infrastructure and Telecommunications (ESPRIT) HALO Lunar Communications System (HLCS) have begun manufacturing the long lead components and will be launched first as a Co-Manifested Vehicle (CMV). The International Habitat (I-Hab) and ESPRIT Refueling Module (ERM) are passing life cycle milestones and include capabilities key for human crewmembers, such as windows, private sleeping quarters, and galley functions. The Logistics Module (LM) may provide a variety of services to Gateway depending on each mission. Requirements for the airlock have been developed, including requests that it support the integrated spacecraft with functions like augmenting heat rejection capabilities, and interfaces with new spacesuits will soon be developed in more detail. As a critical element of the architecture for solar system exploration, Gateway implements key tenets and features of international interoperability standards necessary to operate with multiple visiting vehicles and lunar assets, especially avionics, communications, and docking. Specific choices such as software architecture and standards, power standards, and robotics standards make it possible to utilize heritage or proprietary technology, yet still operate as one spacecraft. Engineering teams are evaluating many possible future missions to be executed at or utilizing the Gateway. The system architecture protects for an evolvable, extensible, and flexible capability. Designing systems robust enough to serve as a cornerstone of exploration activities for decades while remaining adaptable is not without its challenges. The detailed integration activities have revealed challenges and the need to mature key technologies. Refueling is a key component of achieving long life for Gateway, with unique operations to plan, safety concerns to mitigate, and risk reduction activities to conduct to better understand the system. The constraints and impacts of the design of visiting vehicles is also an important concern, with orientation constraints, control of attitude and orbit of the Gateway with docked visiting vehicles. Tradeoffs between robust maintainable systems and lightweight, compact systems must be balanced. Opportunities still exist for adding additional advanced capabilities to increase and extend Gateway’s benefits, such as intravehicular robotics, autonomous Guidance Navigation and Control (GN&C), and augmented control propulsion, heat rejection, or other services.

Molly S Anderson↗
NASA NTRS2024

Design, Development, and Use of a Lunar Lander Simulation for NASA's Artemis Program

This paper describes the design, development, and initial use of a generalized and configurable lunar lander simulation to support NASA’s Artemis Program. This simulation is being developed for the Crew Compartment Office (CrewCo) in the Human Landing Systems (HLS) program and is called the HLS CrewCo Lander Simulation (HCLS). The HCLS provides insight into the challenges associated with returning humans to the Moon and the particular difficulties of operating at the Lunar South Pole. A generalized lunar landing spacecraft based on a government reference design has been modeled but the simulation can be modified and adapted to model vendor designs as well. The simulation architecture and toolsets provide a flexible framework that allows for quickly prototyping and evaluating various aspects of a piloted lunar landing system. This includes the modeling of all principal human controlled flight phases: rendezvous and docking with crew transfer systems; docked orbital outpost operations; undocking and lunar transfer; lunar orbital operations; lunar deorbit, descent, and landing (DDL); lunar surface operations; lunar ascent; and return to the orbital outpost. The flexibility of the simulation allows for the integrated evaluation of potential vehicle subsystems, crew displays, guidance and control modes, and trajectory designs. The purpose of the HCLS is not to design the ideal lunar lander, but rather to understand the strengths and weaknesses of vehicle design choices.

Edwin Z Crues↗
NASA NTRSDate not supplied

A Crew and Logistics Lander for the Common Habitat Architecture

The Common Habitat Architecture is a conceptual study that explores the use of a large habitat derived from the Space Launch System (SLS) liquid oxygen tank as a core habitation element that can be used for crew missions or training in 0g, 1/6g, 3/8g, and 1g. This is not part of current NASA Artemis mission planning, but instead represents an architecture that could potentially follow after the Artemis missions and initial human Mars landings. This architecture leverages Starship-derived vehicles for crew landing on and ascent from the Moon and Mars in support of long-duration surface missions with pressurized crew transfer baselined as a nominal capability. This is not the Human Landing System variant of Starship but represents a number of modifications to enable long-duration surface missions with an eight-person crew size. A rapid brainstorming study was conducted in February of 2021, using only public data, to identify options to deliver the 90-ton Common Habitat to the surface and emplace it at the intended habitation site. This study compared three lunar lander concepts and three Mars lander concepts before ultimately selecting the SpaceX Starship as the most viable lander. The Common Habitat Architecture assumes that this Starship variant can further be modified for crew and cargo delivery, assuming that the use of a common system will lead to cost benefits. It is assumed that the Starship will expend too much propellant in landing crew and logistics to be able to launch, given the assumed absence of surface propellant production. Consequently, a separable ascent stage is used for crew ascent. The pressurized elements of this modified Starship are discussed: Starship Ascent Module, Airlock, Transfer Tunnel, Pressurized Crew Transfer Module, and Logistics Modules. For each element, a description, dimensions, rough mass estimates, core capabilities, and design features are presented. Key mechanisms and internal structures of the starship are also discussed. This will include flame diverters for the ascend module, the orbital docking hatch, Pressurized Crew Transfer Module Garage door, Starship Ascent Module fairing, flame diverter blow-out panels, Pressurized Crew Transfer Module lift system, logistics module lift system, contingency crew ascent via the logistics module lift system, internal catwalks, and structural interfaces. Concept of Operations will be discussed for both Moon and Mars. This will include in-space crew rendezvous and transfer, crewed landing, shirtsleeve crew transfer, crew departure, contingency surface operations, and final element disposition. Key differences for Mars will be discussed, such as the Martian atmosphere, dust storms, the absence of crew handover, and Deep Space Exploration Vehicle rendezvous. Contingency microgravity maintenance access will also be discussed. This work will demonstrate viable pressurized crew transfer with a Starship-based lander architecture. Forward work includes Garage lighting and camera systems, Starship Ascent Module propulsion system and docking port trades, contingency habitation trades, and mass/power equipment estimation. Finally, forward work includes developing a heavy cargo return system derived from the Crew and Logistics Starship. The goal of this system is the return of at least 10,000 kg payloads from the surfaces of the Moon and Mars.

Lunar Lander↗
NASA NTRSDate not supplied

Future Homes in Space: Development of Concepts for Exploration Space Habitats

NASA’s Artemis campaign seeks to return humans to the moon and establish a sustained presence on the lunar surface. This session will emphasize how habitation capabilities on the moon and in cislunar space can potentially contribute to the sustainability objectives of Artemis. Habitable elements represent opportunities to enable longer duration stays, increase the number of crew members present, enhance science and utilization activities, drive technology development for future Mars exploration, perform analog missions, and fuel economic opportunities for US industry. Panelists include Paul Kessler (NASA Marshall Space Flight Center, deputy lead for lunar surface habitation); Andrew Choate (NASA Marshall Space Flight Center, Mars habitation lead); Krystofer Dudzinski (NASA Marshall Space Flight Center, a space architect within the MSFC Advanced Concepts Office); and Larry Toups (retired from NASA Johnson Space Center, currently an adjunct professor at University of Houston in space architecture). The panel is moderated by Tracie Prater (NASA Marshall Space Flight Center, Habitation Systems Development Office). The panel will begin with an overview of the history of habitation concepts and an academic perspective on general considerations in space habitat design (Larry Toups). Paul Kessler and Andrew Choate will introduce NASA’s principle of “architecting from the right” to help define objectives for Artemis missions, needs/characteristics, use cases, and functions (as published in the agency’s Architecture Definition Document) and provide perspective on how this principle informs habitation concept development work. NASA panelists will discuss key engineering challenges identified for developing, deploying, and operating habitable assets on the lunar surface and/or in deep space. These may include dust mitigation, outfitting of inflatable softgoods (for concepts which may use softgoods as a primary structural material), survival in lunar darkness, human health and performance considerations, maintenance/repair/sparing, and autonomy. These identified challenges represent risks for habitation systems development and relate closely to capability gaps identified by the agency. While the work of NASA Marshall Space Flight Center’s habitation development office is primarily focused on habitats which are launched from earth pre-integrated (referred to as Class I in the framework previously developed by NASA space architects Kennedy/Cohen) or launched from earth and deployed at the point of use (Class II), there is also extensive work in NASA, academia, and companies on constructed habitats, which would be built on a planetary surface using indigenous resources (Class III habitats). Panelist Krystopher Dudzinski will discuss potential evolutionary pathways from Class I and Class II habitats to Class III habitats, unique and common architectural challenges within each habitat class, and key gaps in implementing Class III habitats from an architectural perspective. NASA panelists and the moderator will also provide an overview of partnership opportunities and avenues for further engagement to advance habitation systems for the SpaceCom audience. NASA is currently developing notional concepts for a lunar surface habitat and Mars transit habitat, which will be discussed during this panel session and used as examples. These concepts represent options for habitation system design and are a point of departure. They do not represent a final plan or formal recommendation on the part of the agency. Based on the most recent analysis cycle, NASA’s lunar surface habitat (SH) concept nominally supports two crew members for 30 days, with the capacity to support four crew during a surge period where crew will swap between the SH and another surface asset, such as a pressurized rover. This example design has a metallic airlock for ingress/egress and the upper portion is an inflatable material system which serves as the habitation module. The notional interior of the habitat is a three-deck layout/configuration which supports all crew mission functions, including exercise, stowage, extravehicular activity (EVA), sleep, hygiene waste collection, maintenance and repair, and meal preparation. Under analysis assumptions for habitation, the Mars Transit Habitat (TH) concept would support four crew on an up to 1,200 day Mars mission. One option for the concept is to initially dock Transit Habitat at Gateway, where it can be used to increase the duration of crew stays in cislunar space and perform shakedown and analog missions prior to a Mars departure. One challenge in longer duration missions which involve both surface exploration and transit is understanding crew adaptation when transitioning between partial gravity and microgravity environments. TH at Gateway offers an opportunity to study this transition and in doing so reduce risks associated with future Mars exploration. Like lunar SH, the most recent analysis cycle concept of a Mars TH is a hybrid structure design, with a metallic section supporting EVAs, axial/radial docking, and Safe Haven capabilities, and an inflatable softgoods structure for the primary habitation function. Interior layouts to optimize crew usability and livability are currently under trade. The panel will include presentation material, but also seeks to engage the audience in a highly interactive conversation regarding the potential role for habitation in future exploration initiatives. Potential topics for discussion include the influence of the crew experience on habitation systems design and livability/usability considerations, the benefits of space habitation development in terrestrial applications, and challenges and opportunities in “feeding forward” lunar surface habitation systems development to Mars exploration.

space habitats↗
NASA NTRSDate not supplied

Perturbation Modeling and Navigation Tuning for a Crewed Station in Near Rectilinear Halo Orbit

NASA's Gateway program will build a crew-tended station in an Earth-Moon Near Rectilinear Halo Orbit (NRHO) to support deep space missions to the lunar surface and heliocentric space. The station in the NRHO will be visited by crewed vehicles including lunar landers that are high mass relative to Gateway. Docking events with large vehicles induce significant thruster plume and docking contact velocity perturbations. Crewed vehicles induce significant venting perturbations that can stress the navigation filter's ability to remain converged about an estimated state. The torques that arise from venting and lunar gravity gradient require reaction control system (RCS) thruster intervention, which themselves induce a velocity perturbation. The best method to model RCS thruster perturbations is currently in development. This paper simulates different RCS perturbation models, schedules, and an increasing magnitude to investigate the navigation sensitivity to different RCS perturbation models. From the RCS perturbation models simulated, a worst-case scenario is chosen for further scrutiny. The navigation filter is further tuned to handle the most disruptive perturbation modeling and the resulting performance is analyzed.

Navigation↗
NASA NTRS2024

MAGIK Animation of Robotic Operations for Flight SpaceX-30 to ISS

The MAGIK Robotic analysis team provides kinematic feasibility assessments for the ISS and has produced an animation to evaluate Extravehicular Robotics (EVR) activities for the SpaceX (SpX)-30 flight. Shown EVR activities are preliminary and final operations will be developed by Flight Operations Directorate (FOD) Robotics (ROBO). The animation also displays the current ISS configuration at the time of the flight. Flight SpX-30 includes a SpaceX Cargo Dragon vehicle docked to Node 2 Zenith (N2Z) International Docking Adapter (IDA) and consists of the delivery of the Pump Module (PM) Integrated Assembly (IA). Robotic operations shown include the Special Purpose Dexterous Manipulator (SPDM) based on the Space Station Remote Manipulator System (SSRMS) for Trunk extraction of the PM IA, maneuvering to the External Stowage Platform 3 (ESP-3), temporary removal of the Control Moment Gyro (CMG) from ESP-3 Site 4, install of the PM IA at ESP-3 Site 3 and re-install of the CMG to ESP-3 Site4. There is no disposal payload for this flight.

ISS↗
NASA NTRS2024

Design, Development, and Use of a Lunar Lander Simulation for NASA’s Artemis Program

This paper describes the design, development, and initial use of a generalized and configurable lunar lander simulation to support NASA’s Artemis Program. This simulation is being developed for the Crew Compartment Office (CrewCo) in the Human Landing Systems (HLS) program and is called the HLS CrewCo Lander Simulation (HCLS). The HCLS provides insight into the challenges associated with returning humans to the Moon and the particular difficulties of operating at the Lunar South Pole. A generalized lunar landing spacecraft based on a government reference design has been modeled but the simulation can be modified and adapted to model vendor designs as well. The simulation architecture and toolsets provide a flexible framework that allows for quickly prototyping and evaluating various aspects of a piloted lunar landing system. This includes the modeling of all principal human controlled flight phases: rendezvous and docking with crew transfer systems; docked orbital outpost operations; undocking and lunar transfer; lunar orbital operations; lunar deorbit, descent, and landing (DDL); lunar surface operations; lunar ascent; and return to the orbital outpost. The flexibility of the simulation allows for the integrated evaluation of potential vehicle subsystems, crew displays, guidance and control modes, and trajectory designs. The purpose of the HCLS is not to design the ideal lunar lander, but rather to understand the strengths and weaknesses of vehicle design choices.

James Gentile↗
NASA NTRS2025

Inflatable Softgoods Design of an Articulating Crew Transfer Tunnel

Future NASA exploration plans call for lunar and Martian surface systems that form a base camp of multiple, pressurized elements. These discrete components, including habitats and pressurized rovers, require interoperability to meet the Artemis Accords and standard docking systems to physically connect elements together. A pressurized, articulating crew transfer tunnel can be used between a rover and habitat to enable shirt-sleeve transfer of crew and cargo, saving valuable crew time and resources. While transfer tunnels have been described in the past, this work details the design of a structural softgoods system that has compliant capability through a proposed docking range of motion. The inflatable softgoods design is based on a zero-hoop stress shape, known as a Taylor surface, that is stacked and truncated to form a unique and flexible configuration. Analytical, non-linear models have been developed to examine and predict the behavior of the structure, and material testing was used to determine the properties that were used in the model. Finally, a sub-scale test article was constructed using the baseline design and pressurized testing is in work. Additional full-scale testing is planned for future years to fully demonstrate the capability of the system.

Tunnel↗
NASA NTRSDate not supplied

Inflatable Softgoods Design of an Articulating Crew Transfer Tunnel

Future NASA exploration plans call for lunar and Martian surface systems that form a base camp of multiple, pressurized elements. These discrete components, including habitats and pressurized rovers, require interoperability to meet the Artemis Accords and standard docking systems to physically connect elements together. A pressurized, articulating crew transfer tunnel can be used between a rover and habitat to enable shirt-sleeve transfer of crew and cargo, saving valuable crew time and resources. While transfer tunnels have been described in the past, this work details the design of a structural softgoods system that has compliant capability through a proposed docking range of motion. The inflatable softgoods design is based on a zero-hoop stress shape, known as a Taylor surface, that is stacked and truncated to form a unique and flexible configuration. Analytical, non-linear models have been developed to examine and predict the behavior of the structure, and material testing was used to determine the properties that were used in the model. Finally, a sub-scale test article was constructed using the baseline design and pressurized testing is in work. Additional full-scale testing is planned for future years to fully demonstrate the capability of the system.

Tunnel↗
NASA NTRS2026

X-Hab 2026: LiDAR-Powered Autonomous Charging Service Capability for Surface Rovers and Systems

This document details the timeline of the LiDAR-Powered Autonomous Charging Service Capability for Surface Rovers and Systems project, initiated by the Fall 2025 semester class and completed by the Spring 2026 semester class. This project focuses on developing a fully autonomous system composed of a mobile surface rover and an induction charging station with a robotic arm, both controlled by their own NVIDIA Jetson Orin Nano. Structural improvements to the rover suspension system and body eliminated excessive camber, reduced stress and strain on the plexiglass body, and improved maneuverability and durability of the rover. The charging station robotic arm was fully redesigned to increase reach while minimizing weight and increasing misalignment tolerance during docking on uneven terrain. Electrical system improvements addressed previous torque and power limitations of both the rover and charging station arm. High-torque servo motors were selected based on updated calculations which incorporated terrain slope and Factor of Safety, enabling zero-point turning for the rover and increased payload capacity of the charging station arm. Significant progress was made in autonomy and perception. The rover now employs 3D LiDAR and SLAM mapping for localization, mapping, and path planning. The Battery Monitoring System (BMS) was created to coordinate battery management between the rover and charging station. The BMS provides continuous monitoring of battery state of charge, temperature, current, and will enable the autonomous initiation, execution, and termination of the charging cycle via Bluetooth communication. Testing of the WIBOTIC induction charging system demonstrated reliable power transfer under both aligned and misaligned conditions. This project demonstrated the ability of an autonomously navigating surface rover to independently plan a path to the charging station, dock, and the charging station to autonomously deploy a robotic charging arm and initiate charging of the rover. This work details the progress made to demonstrate the feasibility of autonomous surface rover navigation and recharging systems.

Megan Steele↗
DOE OSTI2021

Controlled cyclization of peptoids to form chiral diketopiperazines

The present disclosure provides improved methods for controlled cyclization of peptoid dimers to form N,N′-2,5-diketopiperazines (N,N′-2,5-DKPs) with significant selectivity. In at least some examples, selectivity is based on a serendipitous conglomeration of slow exchange of amide rotamers, steric repulsion from the degree of α-substitution, and the geometric bulk of an amine nucleophile. By varying reaction conditions, the selectivity of the reaction and formation of a particular N,N′-2,5-DKP can be switched. The cyclization works in the presence of a variety of protection groups and diverse functionalities. The teachings herein provide techniques for synthesizing N,N′-2,5-DKPs that can be readily docked with drug candidates for shuttling across the blood brain barrier. This method provides a facile way to produce substituted DKPs containing groups ready for post-modification to include docking drug candidates.

Williams, Robert F.↗
DOE OSTI2022

Portable aircraft controller devices and systems

A portable computerized device for an aircraft control system includes an input system for inputting commands, a device display for displaying information on the computerized device, a processor, a wireless communication module, and a non-transitory computer readable medium comprising computer executable instructions, the computer executable instructions configured to cause the processor to perform a method. The method can include detecting whether the portable computerized device is in a cockpit state such that the portable computerized device is in and/or docked to an aircraft cockpit or if the portable computerized device is in a remote state such that the portable computerized device is not in an aircraft cockpit or is not docked to an aircraft cockpit. If the portable computerized device is determined to be in a remote state, the method includes operating the remote device in a remote mode. If the portable computerized device is determined to be in a cockpit state, the method includes operating the device in a local mode.

Sahay, Prateek↗
DOE OSTI2023

PTM‐Psi : A python package to facilitate the computational investigation of p ost‐ t ranslational m odification on p rotein s tructures and their i mpacts on dynamics and functions

Abstract Post‐translational modification (PTM) of a protein occurs after it has been synthesized from its genetic template, and involves chemical modifications of the protein's specific amino acid residues. Despite of the central role played by PTM in regulating molecular interactions, particularly those driven by reversible redox reactions, it remains challenging to interpret PTMs in terms of protein dynamics and function because there are numerous combinatorially enormous means for modifying amino acids in response to changes in the protein environment. In this study, we provide a workflow that allows users to interpret how perturbations caused by PTMs affect a protein's properties, dynamics, and interactions with its binding partners based on inferred or experimentally determined protein structure. This Python‐based workflow, called PTM‐Psi , integrates several established open‐source software packages, thereby enabling the user to infer protein structure from sequence, develop force fields for non‐standard amino acids using quantum mechanics, calculate free energy perturbations through molecular dynamics simulations, and score the bound complexes via docking algorithms. Using the S ‐nitrosylation of several cysteines on the GAP2 protein as an example, we demonstrated the utility of PTM‐Psi for interpreting sequence–structure–function relationships derived from thiol redox proteomics data. We demonstrate that the S ‐nitrosylated cysteine that is exposed to the solvent indirectly affects the catalytic reaction of another buried cysteine over a distance in GAP2 protein through the movement of the two ligands. Our workflow tracks the PTMs on residues that are responsive to changes in the redox environment and lays the foundation for the automation of molecular and systems biology modeling.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Unraveling the Hsp70-ROS-autophagy axis in pentachlorophenol-challenged lung and liver epithelial cells

Pentachlorophenol (PCP) was extensively utilized as an organochlorine pesticide and wood preservative in the United States from the 1930s until the Environmental Protection Agency (EPA) imposed restrictions due to concerns about its toxicity and potential carcinogenic properties. Although it is no longer widely used, PCP remains a concern due to its environmental persistence and potential for long-term health effects. Significant occupational and environmental exposures have likely occurred, with the health and economic costs of PCP exposure potentially being substantial given its known toxicity. Notably, PCP exhibits rapid absorption through both the skin and respiratory system and has been shown to cause hepatotoxicity, developmental toxicity, immunotoxicity, irritation, and carcinogenicity in laboratory animal studies. PCP exposure induces oxidative stress, a key mechanism underlying its inflammatory and toxic effects, which can activate cellular stress responses including upregulation of heat shock protein 70 (Hsp70). Previous studies in lung and liver epithelial cells have shown that Hsp70 and oxidative stress play pivotal roles in triggering autophagy. This study establishes the critical role of the Hsp70-reactive oxygen species (ROS)-autophagy axis in regulating cellular responses to PCP exposure in human alveolar (A549) and liver carcinoma (HepG2) epithelial cells. Our research elucidated the molecular mechanisms underlying PCP's cellular effects, demonstrating that its exposure resulted in increased expression of autophagy-related proteins (Beclin-1, LC3B, ATG12, and ATG16), subunits of NADPH oxidase (NCF-1, NCF-2, NOX2, and Rac), and antioxidant proteins (SOD and GPx) in both lung and liver cell types. Notably, PCP augmented the interaction between Hsp70 and the autophagy regulator Beclin-1. Pretreatment with the ROS inhibitor N-acetylcysteine or Hsp70 knockdown markedly reversed PCP-induced responses. Our in-silico protein–protein docking analysis and molecular dynamics simulation studies revealed enhanced interactions and/or stable confirmations maintained throughout the simulations for TLR4-Hsp70 and Hsp70-Beclin-1 complexes in the presence of PCP. These findings provide a strong foundation for future studies, employing in vivo experimental models and human populations to identify promising targets for PCP-induced toxicity and cellular injury. As a result, these findings may have far-reaching implications for public health and environmental policy, ultimately leading to the identification of biomarkers and the development of more effective interventions for environmentally induced toxicity and diseases.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2020

Discovery of multidrug efflux pump inhibitors with a novel chemical scaffold

Multidrug efflux is a major contributor to antibiotic resistance in Gram-negative bacterial pathogens. Inhibition of multidrug efflux pumps is a promising approach for reviving the efficacy of existing antibiotics. Previously, inhibitors targeting both the efflux transporter AcrB and the membrane fusion protein AcrA in the Escherichia coli AcrAB-TolC efflux pump were identified. In this work we use existing physicochemical property guidelines to generate a filtered library of compounds for computational docking. We then experimentally test the top candidate coumpounds using in vitro binding assays and in vivo potentiation assays in bacterial strains with controllable permeability barriers. We thus identify a new class of inhibitors of E. coli AcrAB-TolC. Six molecules with a shared scaffold were found to potentiate the antimicrobial activity of erythromycin and novobiocin in hyperporinated E. coli cells. Importantly, these six molecules were also active in wild-type strains of both Acinetobacter baumannii and Klebsiella pneumoniae, potentiating the activity of erythromycin and novobiocin up to 8-fold.

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

Drugging the entire human proteome: Are we there yet?

Each of the ~20 000 proteins in the human proteome is a potential target for compounds that bind to it and modify its function. The 3D structures of most of these proteins are now available. Here, we discuss the prospects for using these structures to perform proteome-wide virtual HTS (VHTS). Furthermore, we compare physics-based (docking) and AI VHTS approaches, some of which are now being applied with large databases of compounds to thousands of targets. Although preliminary proteome-wide screens are now within our grasp, further methodological developments are expected to improve the accuracy of the results.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Design, synthesis and biological evaluation of a new series of thiazolyl-pyrazolines as dual EGFR and HER2 inhibitors

Epidermal growth factor receptor (EGFR, also known as HER1) and HER2, prominent members of receptor tyrosine kinase (RTK) superfamily, have been reported as diagnostic or prognostic markers in tumor progression. Based on the importance of molecular hybridization of pyrazoline and thiazole scaffolds in the discovery of potent anticancer agents, new thiazolyl-pyrazoline derivatives (3a-v) were synthesized and screened for their cytotoxic effects on A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma and A375 human melanoma cell lines. 1-(4-(4-Fluorophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3c),1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3f) and 1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-piperidinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3q) were found as the most potent anticancer agents against A549 and MCF-7 cell lines compared to erlotinib. Compound 3q also showed moderate cytotoxic activity against A375 cell line. Moreover, these compounds exert a cancer cell–selective action against Jurkat cell line posing no toxicity on peripheral blood mononuclear cells (PBMCs). In order to enlighten the mechanism of action underlying anticancer activity, compounds 3c, 3f and 3q were investigated for their apoptotic effects on A549 and MCF-7 cell lines and inhibitory potencies against eight different RTKs including EGFR and HER2 compared to erlotinib. The results indicated that compounds 3f and 3q induced apoptosis in both cell lines and showed significant EGFR inhibitory activity with IC50 values of 4.34 ± 0.66 μM and 4.71 ± 0.84 μM, respectively when compared with erlotinib (IC 50 = 0.05 ± 0.01 μM). Besides, compound 3f also inhibited HER2 notably with an IC 50 value of 2.28 ± 0.53 μM making it a dual EGFR and HER2 inhibitor. Molecular docking studies, which were conducted to support the in vitro assays, pointed out that compound 3f showed high affinity into the ATP binding sites of EGFR and HER2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

The structure of a contact-dependent growth-inhibition (CDI) immunity protein from Neisseria meningitidis MC58

Contact-dependent growth inhibition (CDI) is an important mechanism of intercellular competition between neighboring Gram-negative bacteria. CDI systems encode large surface-exposed CdiA effector proteins that carry a variety of C-terminal toxin domains (CdiA-CTs). All CDI + bacteria also produce CdiI immunity proteins that specifically bind to the cognate CdiA-CT and neutralize its toxin activity to prevent auto-inhibition. Here, the X-ray crystal structure of a CdiI immunity protein from Neisseria meningitidis MC58 is presented at 1.45 Å resolution. The CdiI protein has structural homology to the Whirly family of RNA-binding proteins, but appears to lack the characteristic nucleic acid-binding motif of this family. Sequence homology suggests that the cognate CdiA-CT is related to the eukaryotic EndoU family of RNA-processing enzymes. A homology model is presented of the CdiA-CT based on the structure of the XendoU nuclease from Xenopus laevis . Molecular-docking simulations predict that the CdiA-CT toxin active site is occluded upon binding to the CdiI immunity protein. Together, these observations suggest that the immunity protein neutralizes toxin activity by preventing access to RNA substrates.

59 BASIC BIOLOGICAL SCIENCES↗