Helping to End Addiction Long-term (HEAL): New Chemical Structures for Pain, Addiction and Overdose Targets

帮助长期戒除成瘾 (HEAL)：针对疼痛、成瘾和药物过量目标的新化学结构

• 批准号: 10908194
• 负责人: Samuel Michael
• 金额: $ 397.09万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10908194
• 关键词: 3-Dimensional; Acceleration; Address; Affect; Algorithms; Analytical Chemistry; Animal Model; Automation; Baltimore; Biological; Biological Assay; Biological Process; Biological Sciences; Biology; Cell model; Cells; Chemical Structure; Chemicals; Chemistry; Chromatography; Clinical Trials; Cloud Computing; Collaborations; Complex; Computer software; Cooperative Research and Development Agreement; County; Data; Data Analyses; Data Analytics; Development; Devices; Diagnosis; Disease; Ecosystem; Emerging Technologies; Equilibrium; Equipment; Equipment and supply inventories; Event; Future; Glass; Goals; Government; Health; Helping to End Addiction Long-term; Human; Human Biology; Infrastructure; Intellectual Property; Intelligence; Interdisciplinary Study; Intervention; Intuition; Laboratories; Laboratory Chemicals; Lead; Legal patent; Link; Liquid substance; Machine Learning; Manuals; Maryland; Methods; Microfluidics; Modeling; Modernization; National Center for Advancing Translational Sciences; Opiate Addiction; Organic Chemistry; Overdose; Pain; Pathway Analysis; Patients; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Play; Preparation; Process; Production; Professional Organizations; Public Domains; Public Health; Reaction; Reagent; Reproducibility; Research; Research Personnel; Risk; Role; Route; Running; Sampling; Science; Scientist; Secure; Services; Solid; Specific qualifier value; Standardization; Structure; System; Systems Biology; Technology; Testing; Therapeutic; Time; Tissue Microarray; Tissues; Translational Research; Translations; United States National Institutes of Health; Universities; Vision; Work; addiction; application programming interface; bioprinting; blockchain; chemical reaction; chemical synthesis; computational platform; computerized tools; cost; dashboard; data analysis pipeline; data ingestion; data integration; data management; data sharing; density; design; drug candidate; effective therapy; efficacy study; evaporation; evidence base; experimental study; first-in-human; high throughput screening; human model; implementation cost; improved; in vivo evaluation; indigo dye; induced pluripotent stem cell; innovation; innovative technologies; instrument; instrumentation; knowledgebase; manufacture; models and simulation; new technology; next generation; novel; novel strategies; novel therapeutics; open source; operation; opioid epidemic; opioid misuse; opioid use; opioid use disorder; preclinical efficacy; predictive tools; programs; prototype; research and development; safety study; screening; sensor technology; sharing platform; simulation; technological innovation; tool; virtual platform

ASPIRE Integrated Computational Platform The ASPIRE Integrated Computational Platform (AICP) is being developed that will provide the chemical intelligence to support automated, high throughput synthesis. The AICP has a modular design, in the center of which is a Reaction Data Management Application Programming Interface (RDM API). Several components of the AICP were developed as prototypes and has been deployed in various research and development projects. The functionalities of the AICP currently cover a reaction data ingestion and processing pipeline, RXNO annotation of reactions, evidence-based synthesis route design, reaction data analytics and integrating yield information. We developed a novel technology to protect Intellectual Property (IP) sensitive chemical information with the help of blockchain technology. We prepared to integrate reaction and condition prediction methods into the AICP, and this task is among highest priority tasks for the next phase of the AICP development. The RDM API will play a pivotal role for integrating solution provided by the future awardees related to the ASPIRE virtual platform RFA. The Reaction Knowledgebase currently stores 100K public domain reaction data. We started a collaborative project to showcase how the AICP can transform probe development projects in the structure optimization phase. We intend to integrate NCATS ELN data into the internal Reaction Knowledgebase, upon the approval of NCATS stakeholder. Building on our blockchain technology we developed a prototype of a Reaction Portal (RP) which aims to be an experiment designer, data analysis and data sharing platform, enabling NCATS scientist and external collaborators to securely generate, store, analyze and exchange their data. A major component of this portal, the Network Widget has been developed. Besides allowing chemists to design and analyze synthesis routes, it was designed to be repurposed in another network analysis related research settings, i.e. in systems-biology related projects. 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. Numerous experiments are being conducted on the UnChained Labs platform in addition customizations that will facilitate analysis and applications of open source Bayesian optimization algorithms. The analytical processing platform purchased from Virscidian to be used to process reaction screening data has been expanded to support the QC operations of Compound Management. Chemical Inventory 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. From this work a set of requirements have been drafted along with a functional specification to guide the development of a next generation chemical inventory system. Provisional Patent Applications on Innovative hardware and software 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. Provisional patents have been submitted for: a) a novel workstation that conducts cartridge-based workup processes for chemical reactions; b) a device used for inerting the headspace of glass reactors during reaction amenable to both manual and automated use; c) a software application based on block chain technology to manage and protect intellectual property generated in the laboratory. In addition a PCT application is being pursued for the development of a versatile batch evaporator for use at both at the bench or at scale in a fully automated implementation. Significant equipment and processes progress made. Core integrated benchtop chemistry capabilities include serial/batch processing for SPE/Chromatography, evaporation, integrated balance, reaction platforms, fed by in-house designed high density storage connected to in-house inventory software as well as compound management. Automated qNMR/NMR sample prep with Analytical chemistry using Sirius MultiTasker and OmniTasker. Automated purification module design complete. 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. Collaborative efforts on the Indigo platform has led to significant hardware and software improvements. IOT - NCATS Laboratory Dashboard (Azure integration fully functional) 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 standardized the exchanges of consumables and data between workstations typically used in a chemistry laboratory setting. These changes will significantly improve the continuity of experiment execution by enabling remote connectivity to lab instrumentation while adding important experimental context to execution of research workflows. Discrete Event Simulation Modeling NCATS has acquired a new tool to assist in the design of complex integrated automation solutions. The tool consists of a software application (ProModel) that allows one to create discrete event model simulations to examine how complexes processes will interact with one another under a complex variety of conditions. Such simulations to better assess how complex integrated systems are likely to interact under a variety of controlled variable distribution of parameterized events to understand such things as realistic throughput estimates, identify and address process bottlenecks, balance process loads across entire systems, plan staffing support scenarios, identify optimal process layouts and better anticipate space utilization cost of implementation and support, etc. Synthetic Biomolecular Diversity Initiative Biomolecular synthesis technologies can employ computational tools for the prediction of structures and synthetic routes, along with automated synthesis and purification in self-contained systems for early testing as well as production of GMP-like materials for in-vivo testing. Two significant collaborative programs continue to make progress in this space: a) MyTide Therapeutics have successfully prepared a first batch of peptides in support of Jim Ingleses ANP1 Modulator program to be tested in the coming weeks; b) Center for Advanced Sensor Technology at University of Maryland Baltimore County has recently completed a pilot synthesis of Griffithsin using cell-free lysate systems in support of work being done to prove the value of self-contained benchtop synthesizer for biolog