Vision for ASPIRE
With the A Specialized Platform for Innovative Research Exploration (ASPIRE) initiative, NCATS seeks to accelerate preclinical drug discovery by integrating automated synthetic chemistry, high-throughput biology and information technologies to help scientists study unexplored biologically active chemical space.
Credit: National Center for Advancing Translational Sciences
The overall goal of ASPIRE is to enable real-time translational science by combining expertise in chemistry, biology, pharmacology, automation and AI/ML to provide a rapid decision-making platform to advance lead molecules to the clinic.
More information about the capabilities of the intramural laboratory will be added in the coming months.
Learn more about ASPIRE capabilities in the following areas:
Credit: National Center for Advancing Translational Sciences
ASPIRE’s biology component aims to establish a biological activity profile library of molecules in near real time to enable the identification of novel, next-generation molecules with drug-like properties. Early profiling will include solubility, biochemical and cellular activity using pharmacologically relevant assay reagents, and assay platforms. Additional testing will include target engagement, biophysical properties, in vitro PK/PD/toxicology and confirming biological activities in human induced Pluripotent Stem Cells (hiPSC)-derived 3D printed tissues or organoids as necessary for molecular scaffolds of interest. A key goal of the biology component is the rapid turnaround of test data and biological annotations.
The ASPIRE biology platform will integrate existing high-throughput screening and lead optimization automation at NCATS with emerging state-of-the-art bioanalytical and imaging technologies to enable comprehensive “pharmacological intelligence” on molecular libraries.
Additionally, the ASPIRE biology platform will entertain new synthetic biology collaborations to generate molecular diversity, cell and macromolecular reagents to enable screening, and lead optimization in real time.
The chemical synthesis component of ASPIRE will focus on the development of core expertise and technologies involved in reaction screening, which automatically will be translated directly into successful reaction batch production of synthetic targets. A key aim is to facilitate the entire synthesis workflow, from design to biological evaluation, with minimal human intervention through the adoption of strategic protocol standardization parameters. The goal is to implement innovative technologies that accelerate researchers’ ability to advance chemical synthesis automatically and to allow researchers to focus entirely on higher order intellectual activities that lead to meaningful discoveries and hypothesis generation.
Informatics research in ASPIRE is focused on the creation of a “chemical intelligence” powered integrated computational platform to drive the autonomous design and synthesis of novel therapeutics and the exploration of unknown chemical space and knowledge. To accomplish this, the ASPIRE initiative is building a high-quality reaction knowledgebase via the integration of historical and high-throughput synthesis data. With the help of AI/ML methods — including network analysis, traditional machine learning and deep learning techniques — ASPIRE aims to develop novel computational methods for the design and synthesis of novel bioactive molecules of therapeutic potential. The methods will form an automated computational pipeline addressing molecular modeling, retrosynthesis planning, reaction execution, and optimization of reaction conditions and the properties of the target molecules.
ASPIRE prioritizes the early dissemination of novel reaction informatics methods and potentially public data sets. In the future, ASPIRE will host a collection of source code repositories and computational tools for both NCATS and extramural researchers to use.
Collaborations are critical to the successful implementation of ASPIRE at NCATS. The project intends to develop and share tools, technologies and standardized protocols in automation, chemistry, biology, pharmacology and informatics, both internally and in partnership with extramural researchers. These assets will be openly shared with appropriate protections for intellectual property rights for registered institutions willing to collaborate.
Partnerships can be managed with Confidentiality Agreements (CDA), Research Collaboration Agreements (RCA) and other instruments compatible with individual research institutions.
One of the aspects of automation that is most appreciated, particularly in the life sciences, is its ability to relieve researchers of routine tasks that can be readily developed into well-orchestrated processes run by robots. In addition to allowing scientists more time and opportunity to pursue innovative activities, automation can lead to better reproducibility, which, in turn, leads to more rapid and convincing discoveries. NCATS has extensive experience in the area of robotically executed biological assays and aims to use some of that expertise to improve its ability to synthesize molecules with minimal human involvement, which is a challenge when the goal is to integrate other key aspects of molecular synthesis as well, such as purification, characterization and plating for screening.
NCATS has given much thought to how to develop a proper infrastructure for ASPIRE. One key infrastructure objective is space, and NCATS recently secured the renovation of a 4,400 ft2 open laboratory space to house ASPIRE and supporting technologies. NCATS is designing the space with an eye toward the flexibility, portability and evolution of technology solutions in order to keep pace with the rapidly changing scientific discovery and drug development landscape. Another key infrastructure objective involves developing hardware and software frameworks that can be used as work process standards, which will lead to lower the costs in the development, operation and duplication of the technology elsewhere. NCATS’ ultimate goal is to promote the development of platforms similar to ASPIRE to enhance transdisciplinary collaboration and accelerate the discovery of innovative and effective treatments.
Some publications may require a subscription to access full manuscripts.
Sittampalam GS, Rudnicki DD, Tagle DA, Simeonov A, Austin CP. Mapping biologically active chemical space to accelerate drug discovery. Nat Rev Drug Discov. 2019;18 (2):83–84. https://www.nature.com/articles/d41573-018-00007-2.
Godfrey AG, Michael SG, Sittampalam GS, Zahoránszky-Köhalmi G. A perspective on innovating the chemistry lab bench. Front Robot AI. 2020;7:24. https://www.frontiersin.org/articles/10.3389/frobt.2020.00024/full.
Zahoránszky-Köhalmi G, Siramshetty VB, Kumar P, et al. A workflow of integrated resources to catalyze network pharmacology driven COVID-19 research. BioRxiv 2020.11.04.369041v1 [Preprint]. 2020. Available from: https://www.biorxiv.org/content/10.1101/2020.11.04.369041v1.
Zahoránszky-Köhalmi G, Wan KK, Godfrey AG. Hilbert-curve assisted structure embedding method. ChemRxiv 11911296.v1 [Preprint]. 2020. Available from: https://doi.org/10.26434/chemrxiv.11911296.v1.