HEAL: New Chemical Structures for Pain, Addiction and Overdose Targets

点击翻译按钮获取中文摘要

ELN Extraction -> Data Curation -> Reaction Analytics Dashboard Prototype A workflow was developed and executed for extraction and curation of chemical reaction data from NCATSs eLN. A subset of non-proprietary data was selected for detailed curation and annotation with the goal of creating a dataset suitable for machine learning purposes. The goal is to create a reaction analytics dashboard to better guide reaction development and more effectively enable target molecule synthesis. Finalized installation of Reaction Screening platform Installation of an inhouse reaction screening platform consisting of a dual liquid- and solid-dispensing workstation provided by UnChained Laboratories and a large glovebox provided by MBraun for preparing, conducting, and processing high-throughput reaction screening experiments under completely inert conditions. Chemical Inventory -> EDA, curation and annotation completed In preparation for seamless integration of reaction preparation for automated synthesis, the complete chemical inventory was downloaded, analyzed, curated, and annotated for the purposes of modeling of a next generation inventory management system for chemical synthesis. Patent drafts initiated on SPE and Batch Evaporator The vision of the ASPIRE project is to provide a homogenous integration link between the regular laboratory and a fully integrated, nearly-autonomous system. To accomplish this, smaller-scale projects that address gaps in the medicinal chemistry workflow have been implemented to redesign the tools that chemists use at the bench allowing translation to automatic setup and execution. Such tools include a solid phase extractor to facilitate workup of reactions to tools that permit direct and scalable evaporation from select containers such as final product scintillation vials and the reaction vessels themselves. Strateos CRADA -> Indigo SAT NCATS initiated a collaboration with Strateos and in partnership with Eli Lilly to further the development of a flagship reactor system to be featured in both the Lilly Life Sciences Studio and the NCATS ASPIRE facility currently under development. In addition to providing technical implementation and automated function of the Indigo reactor system, the project team intends to work collaboratively to lower the barriers involved in automating chemical synthesis in general. IOT - NCATS Laboratory Dashboard (Azure integration and blockchain pilot started with BurstIQ) A significant component of the ASPIRE project is to create a sustainable ecosystem of integrated technologies that realizes the goal of creating Real-Time Translational Science by accessing and leveraging capabilities offered by modern cloud-computing technologies into more secure, effective, and scalable data sharing strategies and implementations. To this end, we have successfully integrated instrument access through the Azure clouding computing services and initiated a collaboration with IQBurst to study the viability of leveraging blockchain technologies as more effective means of managing the data life-cycle. Flow Chemistry exploration in space (CASIS) NCATS is currently engaged in a four-way collaboration with CASIS, SpaceTango, and Boston University to study flow chemistry in micro-gravity environments on the International Space Station. The study will initially involve studying the execution of iterative peptide synthesis. One of the first targets to be explored will be a four-membered cyclic peptide with known activity as a kappa opioid receptor antagonist with potential for development as a analgesic with lower addiction liability than currently available treatments. Kebotix Collaboration NCATS collaborated with Kebotix, a technology platform company for new chemicals and materials, to enhance productivity of NCATS high-throughput experimentation (HTE) via artificial intelligence-driven optimization of assay conditions for biosynthesis inhibitors. Instead of testing a set of predefined parameters as in the traditional DOE approach, Kebotix uses adaptive optimization to gain more information using fewer experiments and less materials. By employing an advanced proprietary AI-driven optimization algorithm, Kebotix found suitable conditions and optimal assay performance with only 55 measurements with up to 20 running simultaneously. This output was sufficient for the Kebotix algorithm to identify and test the global optimum of the full 294 DOE experiments with a high probability (>95%). NCATS achieved a five-fold reduction in costs for lab supplies and HTE run-time, reduced from 49 hours to just 9 hours. This collaboration serves as a test case for integrating existing NCATS screening technology to operate in an autonomous fashion while being driven by AI/ML techniques. SLAS automated chemistry session NCATS featured prominently in this year's annual SLAS conference (Society for Laboratory Automation and Screening) both as presenters of NCATS research and as key contributors to the organization of the conference with Sam Michael serving as track chair for the Automation and High-Throughput Technologies program, as well as chair for the Open Source Automation session. Further, Alex Godfrey served as session chair for the Automating Chemistry in the Age of AI session. Multiple presentations throughout the conference including both the opening and closing keynote presentations highlighted the impact of powerful machine-learning algorithms on the development of new medicines and the strides being made in automating chemical synthesis to improve the efficiency with which chemical space is explored - both key objectives woven into the ASPIRE program aimed at improving and accelerating the development of pharmacotherapies to treat pain, addiction, and overdose . Synthetic Biomolecular Diversity Initiative This signature program involving synthetic biomolecular diversity and on-demand biologics has been initiated on the ASPIRE platform. The Design-Build-Test-Learn" cycle will be applied to ongoing and new projects at NCATS. This effort will allow NCATS to explore macromolecular diversity and novel biological systems for translational science and research applications. This effort will also help to identify any gaps in the Design-Build-Test-Learn workflow in these labs and implement new automation/ BIO-CAD solutions to close such gaps. A working group consisting of biologists, chemists, informaticians, automation specialists and strategic alliance experts has been established to explore opportunities. A new seminar series has been initiated to engage biologists and identify potential collaborators, products, and companies of interest in areas of DNA printing, cell-free translation, and peptide or protein therapeutics using rapidly evolving synthetic biology technologies. Two collaborations have been initiated in the last 3 months with 1) Mytide Pharmaceuticals for automated peptide synthesis and 2) Center for Advanced Sensor Technology at University of Maryland Baltimore County for exploring the manufacture of therapeutic proteins in milligram to gram quantities using cell-free lysate systems. These technologies can employ computational tools for structure and synthetic route predictions along with controlling synthesis and purification in automated self-contained systems for GMP-like materials for in-vivo testing. These automated systems on the ASPIRE platform can be expanded to other macromolecular diversity collections such as synthetic oligonucleotides, carbohydrates and polysaccharides, fatty acid analogs ,and hybrid macromolecule-small molecule conjugates for therapeutic applications.