The primary challenge of most early stage hit-discovery or scaffold-hopping drug discovery and development projects is to identify novel chemical matter with Freedom to Operate (FTO), while simultaneously optimizing the physico-chemical properties that are crucial for robust activity. This is a multi-parameter optimization (MPO) problem that is difficult to solve and makes the drug discovery process expensive, complex, and time-consuming. Traditional approaches like virtual-screening of large chemical databases, followed by filtering on desired physico-chemical properties, have had limited success since they try to tackle the MPO problem by exploring a very small section of the chemical space which does not confer sufficient diversity and novelty. To overcome the shortcomings of the traditional screening approaches, Iktos has developed a 3D structure-based generative Artificial Intelligence (AI) pipeline, focused on MPO, where the goal is to identify new, easily accessible molecules with drug-like characteristics and high activity on the protein target. The technology uses deep-learning based de novo design algorithms to generate molecules. The generation process is optimized by Reinforcement Learning based on diversity, novelty, quality, synthetic accessibility, and maximizing of 3D scores (docking score, proprietary contact score, 3D-shape similarity with known co-crystalized ligand etc.) of the generated molecules, thus ensuring ligand interactions with key atoms within the protein pocket. This is an iterative AI-based chemical space exploration aimed at designing new chemical structures with optimal 3D scores and physico-chemical properties. Here we demonstrate this technology by identifying compounds with high affinity for an oncology target of known structure (PIM1- kinase). Using a combination of 3D-structure based techniques, parameters, and generative AI pipeline, we successfully identified novel active compounds that are outside the chemical space of the known PIM1-kinase inhibitors. No prior knowledge of existing PIM1-kinase inhibitors was used during the generation. Experimentally, one of the novel Iktos compounds was found to have IC50<1µM and good preliminary ADME properties (logD, solubility, and clearance). Our approach represents a fundamental shift in tackling MPO in early stage drug discovery projects, and improving the chances for success.
POLY in the proud sponsor of the Fourth CME NASA Symposium which Brings Together Industry, Academia, Government and the Public to Enlarge and Enhance the STEM Talent Pool. The goal is to propel cutting-edge developments in chemical sciences to advance human space travel and translate them into new knowledge to improve the lives of people and make their dreams a reality. Join us for these two days packed with inspirational research, industry advances and job trends.
The talk will describe the history and features of the Ladder of Life Detection, a tool intended to guide the design of investigations to detect microbial life within the practical constraints of robotic space missions. To build the Ladder, we have drawn from lessons learned from previous attempts at detecting life and derived criteria for a measurement (or suite of measurements) to constitute convincing evidence for indigenous life. We summarize features of life as we know it, how specific they are to life, and how they can be measured, and sort these features in a general sense based on their likelihood of indicating life. Because indigenous life is the hypothesis of last resort in interpreting life-detection measurements, we propose a small but expandable set of decision rules determining whether the abiotic hypothesis is disproved. In light of these rules, we evaluate past and upcoming attempts at life detection. The Ladder of Life Detection is not intended to endorse specific biosignatures or instruments for life-detection measurements, and is by no means a definitive, final product. It is intended as a starting point to stimulate discussion, debate, and further research on the characteristics of life, what constitutes a biosignature, and the means to measure them.
Several icy moons of the giant planets harbor subsurface oceans. At least one has a chemistry (pH, major elements, redox gradients, simple and macromolecular organic compounds) similar to inhabited places in our ocean. Progress in approaches to searching for life is being infused into ocean moon missions designed to discover either life beyond Earth or the first habitat where life is unseen.
Enceladus Orbilander mission concept for the Planetary Science & Astrobiology Decadal Survey of the National Academies. Credit: M. Neveu/Enceladus Orbilander Concept Study Team/M. Wallace/Applied Physics Laboratory/W0W Inc.
Life on Earth evolved metabolic pathways to fix atmospheric nitrogen to more biochemically available molecules for use in proteins and informational polymers. For this reason, “Follow the nitrogen” has been proposed as a strategy in the search for life on Mars. We discuss detections of fixed nitrogen on Mars by the Mars Science Laboratory (MSL) Curiosity Rover, recent evidence of nitrogen bearing compounds in Martian meteorites, and nitrogen systematics in terrestrial analogs to illuminate the role of nitrogen in the habitability on Mars.
Advancements in composites materials and manufacturing supports the future of space exploration as well as national competitiveness needs. NASA research and development efforts in composites materials over the past 25 years has been well integrated across the TRL spectrum. NASA is seeking to take advantage of spacecraft applications that would benefit from substantial weight savings and important cost savings compared to traditional state of the art materials. This presentation examines past and present NASA R&D efforts, together with the technical and cultural barriers, and future directions of research and innovation.
This presentation examines our research towards engineering CNT networks to realize high mechanical and electrical performance. We discovered the unique geometrically constrained self-assembling and graphitic crystal packing of flattened and aligned CNTs during the stretching process of CNT networks. The new microstructures can improve the ultimate surface contact among the CNTs to substantially improve load transfer and mechanical properties. This feature provides the potential to realize microstructures capable of achieving desired long-range orders, fewer defects, and ordered crystalline packing, which are essential for fully transferring the CNT mechanical and electrical properties into macroscopic composite materials. Figure 1 shows an example of CNT self-assembling in a stretched CNT network.
The evolving demands of the modern world call for new materials with advanced performance and minimal environmental footprint. As the structural complexity of these materials increases, the traditional iterative approach to synthesis, testing, and optimization becomes prohibitively time consuming and labor intensive. Here, I will present an abiotic approach to the discovery of new organic materials inspired by directed evolution. The key advance that makes this approach possible is the discovery of reaction mechanisms that link a stimulus (light) to the target (photophysical) properties.
An ordinary commercial MSLA printer can be harnessed to create a large scale foam manufacturing platform using our novel highly expandable foaming resin. This unique formulation allows for isotropic expansion of printed parts up to 40x (by volume), digital control over density, porosity and cell morphology. Our process represents nearly 2 orders of magnitude improvement over the prior art, and can be accomplished using a low-cost system (under $300) with a simple, commercially available chemical formulation. Our process allows for the fabrication of structures significantly larger than the build volume of the 3D printer which produced them. Complex geometries such as Voronoi structures, functional airfoils, and floatation aids composed of porous foams are presented with videos of their fabrication and testing. The potential applications for our system include architecture, aerospace, energy, and biomedicine. Screening and characterization of resin formulations, print parameters, observed mechanical properties, and resultant foam structure of the printed and expanded foam objects is presented as well.
NASA is rapidly advancing additive manufacturing technology to support NASA missions in space exploration, science, aeronautics, and technology, as well as the aerospace industry, other Government Agencies, and to address related national needs. NASA performs this work at NASA Centers, through contracts/grants and in public private partnerships. NASA’s focus is generally on applied research and development activities where substantial enhancements in NASA mission capabilities are needed. NASA has extensive experience in additive manufacturing technologies with involvement in more than 30 different machine systems in the past 30 years. NASA is taking a lead role in areas specific to NASA missions such as propulsion and in-space manufacturing and not trying to lead in all AM technology areas. NASA’s in-space manufacturing objective is to identify and implement on-demand manufacturing solutions for fabrication, maintenance, and repair required for sustainable Exploration Missions. The Agency portfolio spans a range of mission applications and discipline areas such as computational modeling, design, materials, processes and certification across technology readiness levels/manufacturing readiness levels (TRLs/MRLs).
Miniaturized biosensing devices for point-of-care diagnostics are of upmost importance to ensuring astronaut crew health and safety. As human space missions extend to longer durations, sensor resupply will not be a viable option. By relying on additive manufacturing and simple printing technology, biosensors can be fabricated in space, thus enabling adaptive crew health monitoring on long-duration space missions and habitation. Here we report a generic electrochemical biosensor platform that can be fabricated using a single printer and will require minimal crew time to operate. Functional inks manufactured from carbon nanotubes, gold nanoparticles and silver nanoparticles were used to print a 3-electrode elechemical device. Biosensor devices were fabricated on both paper and Kapton substrates by either a piezo drop-on-demand inkjet printer and an atmospheric pressure plasma jet printer. The working electrodes were functionalized with both aptamer and antibody probes specific to troponin-I and cortisol. Sensor performance was characterized by cyclic voltammetry, differential pulse voltammetry and electrochemical impedance spectroscopy. The results demonstrate that these biosensors can serve a miniaturized, low cost, point-of-care devices for detection of proteins, hormones and other small biomolecules. In the future, these biosensor devices will be fabricated and characterized on the International Space Station and the approach will be evaluated for future in-space manufacturing of point-of-care diagnostic devices.
Two-dimensional polymers (2DPs) are a unique macromolecular architecture that combine covalent connectivity, permanent porosity, and structural regularity. Recently, synthetic advances have led to the production of 2DPs as single-crystals and high-quality films, both of which are ideal for property and device measurements. Here, I will discuss recent findings regarding the thermal, mechanical, optical, and electronic properties of macromolecular sheets. I will also describe first-generation 2DP-based devices, which show promising combinations of behaviors not accessible with other material classes.
Macrocycles that assemble into nanotubes exhibit emergent properties stemming from their low dimensionality, structural regularity, and distinct interior environments. I will present report a versatile strategy to synthesize diverse nanotube structures in a single, efficient reaction by using a conserved building block bearing a pyridine ring. Imine condensation of a 2,4,6-triphenylpyridine-based diamine with various aromatic dialdehydes yields chemically distinct pentagonal [5+5], hexagonal [3+3], and diamond-shaped [2+2] macrocycles depending on the substitution pattern of the aromatic dialdehyde monomer. Modifying these macrocycles to achieve emergent mechanical and transport properties will also be discussed.
Understanding dynamic chemistry systems in Nature inspires chemists to design biomimetic synthetic materials. Disulfide bonds, the bonds that tie peptides, feature their dynamic covalent nature, that is reversible covalent bonds. Here we propose that making polymers with disulfide bonds can be a solution towards intrinsically dynamic materials. Unlike traditional plastics and noncovalent (supramolecular) polymers, poly(disulfides) can simultaneously exhibit chemical recycling ability and excellent mechanical performances. We will focus on the poly(disulfides) derived from thioctic acid, a natural small molecule, to show the promising applications of these intrinsically dynamic materials in self-healing elastomers, adhesives, and actuators.
The fascinating molecular motors and machines that sustain life offer a great source of inspiration to the molecular explorer at the nanoscale. The focus is on the dynamics of functional molecular systems as well as triggering and assembly processes. We design motors in which molecular motion is coupled to specific functions. Responsive behavior will be illustrated in self-assembly and responsive materials with a focus on cooperative action, amplification along multiple length scales and 2D and 3D organized systems. The design, synthesis and functioning of rotary molecular motors and machines will also be presented with a prospect toward future responsive materials.