| NSF Org: |
CHE Division Of Chemistry |
| Recipient: |
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| Initial Amendment Date: | June 24, 2020 |
| Latest Amendment Date: | June 24, 2020 |
| Award Number: | 2033426 |
| Award Instrument: | Standard Grant |
| Program Manager: |
Michel Dupuis
CHE Division Of Chemistry MPS Directorate for Mathematical and Physical Sciences |
| Start Date: | July 1, 2020 |
| End Date: | June 30, 2021 (Estimated) |
| Total Intended Award Amount: | $199,999.00 |
| Total Awarded Amount to Date: | $199,999.00 |
| Funds Obligated to Date: |
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| History of Investigator: |
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| Recipient Sponsored Research Office: |
1275 YORK AVE NEW YORK NY US 10065-6007 (646)227-3273 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
1275 York Ave New York NY US 10065-6007 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): |
Chem Thry, Mdls & Cmptnl Mthds, OFFICE OF MULTIDISCIPLINARY AC |
| Primary Program Source: |
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| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.049 |
ABSTRACT
John Chodera of the Sloan Kettering Institute for Cancer Research is supported by an award from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry to identify the biophysical determinants of inhibition for the SARS-CoV-2 main viral protease (Mpro). Mpro is an essential enzyme in the virus that causes COVID-19. The Chodera lab develops physical models accelerated by inexpensive consumer-grade graphics processing units (GPUs) to predict which small molecules might bind and inhibit disease-relevant proteins. The Chodera lab is part of the Folding@home Consortium, a research collaboration that uses the Folding@home distributed computing environment to run these calculations. This computing resource is donated by a network of volunteers around the world. Recently, in response to the COVID-19 pandemic, Folding@home became the largest computing platform of any kind in the world, with >25M CPU cores and >600K GPUs participating at any given time. The Chodera lab will use Folding@home to integrate computation and experiment to rapidly identify high-affinity inhibitors of Mpro and to elucidate key interactions required for effective inhibition. They work with collaborators at Informatics Matters (a team that works to enumerates synthetically feasible compounds), Enamine (to synthesize compounds), the Diamond Light Source (to crystallize chemical compounds), the London lab at the Weizmann (to assay compounds), and PostEra (to make the results rapidly and publicly available in a manner that can accelerate research on Mpro inhibition in other research laboratories and pharmaceutical companies).
Over the last two months, Folding@home has become the world?s largest computing resource (>2.5 exaflops, >25M CPU cores, >600K GPUs) in service of COVID-19 specific research. John Chodera, a founding investigator in the Folding@home Consortium, and collaborators have established a rapid pipeline to go from the selection of molecules within the 14B compound Enamine REAL Space virtual synthetic library to key biophysical data (X-ray structures and affinities) to SARS-CoV-2 main viral protease (Mpro) with ~2 week turnaround time. His laboratory is now using relative alchemical free energy methods to assess strategies for rapidly progressing an initial set of 68 small molecule X-ray structures from an initial screen for weak inhibitors toward high-affinity ligands. The team also identifies key biophysical determinants of high-affinity ligand binding within the active site of Mpro, and benchmark the propsective accuracy of small molecule force fields to inform the development of next-generation force fields. The laboratory is selecting molecules from Enamine REAL Space to be synthesized, soaked to produce X-ray structures by DiamondMX/XChem, and assayed for Mpro inhibition by the London lab at the Weizmann Institute via collaborations already in place. All computational data is being rapidly disseminated online via the NSF-funded Molecular Sciences Software Institute (MolSSI) COVID-19 Molecular Structures and Therapeutics Hub and the open science COVID Moonshot program to maximize multiple downstream uses for fundamental research and the opportunity for broader impacts in applied and translational areas.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
This RAPID award supported our effort to use Folding@home, a worldwide volunteer distributed computing effort, to aid the prioritization of potent new inhibitors of the SARS-CoV-2 main viral protease, an essential protein in the life-cycle of the virus that causes COVID-19 dieases that is of high interest for the development of new antivirals. This work was done in close collaboration with the COVID Moonshot [http://postera.ai/covid], a global open science collaboration aiming to develop a new oral antiviral to end the COVID-19 pandemic.
Our primary goals were to:
- Learn about the kinds of compounds that could bind tightly to and inhibit the SARS-CoV-2 main viral protease (Mpro) to develop a "chemical atlas"
- Assess the accuracy of current-generation predictive force field based models (alchemical free energy calculations with the public Open Force Field Initiative force fields) to enable researchers to systematically improve their accuracy
- Aid the ability of a rapidly-moving open science drug discovery project to produce a new oral antiviral capable of swiftly bringing an end to the COVID-19 pandemic to enter clinical trials
The award financially supported a software scientist, who engineered the infrastructure required to run high-throughput alchemical free energy calculations on Folding@home to prioritize compound designs submitted by medicinal chemists and scientists around the world to the COVID Moonshot website. In addition, this award funded some of the synthesis of compounds that had been prioritized by these free energy calculations.
Key outcomes:
Advancement to preclinical phase
This RAPID award contributed to the COVID Moonshot open science project rapidly completing the discovery phase for a novel oral SARS-CoV-2 antiviral. The Moonshot has now secured an $11M grant from the Wellcome Trust to enter the preclinical phase to receive approval to begin clinical trials once preclinical safety studies are completed. This work is being carried out under an open-IP model that aims to avoid patenting the antiviral so that manufacturers around the world can produce the therapeutic once it is approved.
The discovery phase is summarized in this preprint:
https://www.biorxiv.org/content/10.1101/2020.10.29.339317v2
Discovery of novel, potent noncovalent compounds with the ability to inhibit the SARS-CoV-2 main viral protease (Mpro):
Compounds prioritized and synthesized by thie RAPID award have activity data [https://covid.postera.ai/covid/activity_data] and structures [https://covid.postera.ai/covid/structures] reported publicly, with all data summarized in this preprint:
https://www.biorxiv.org/content/10.1101/2020.10.29.339317v2
All compounds are available for purchase through Enamine [https://enamine.net/] for research use without the need for a materials transfer agreement.
Folding@home COVID Moonshot dashboards:
Every batch of calculations ("Sprint") is summarized in a public web dashboard displaying the results of calculations, allowing the Moonshot medicinal chemistry team to select optimal molecules and researchers around the world to analyze this data. The most recent example is Sprint 10:
https://fah-public-data-covid19-moonshot-sprints.s3.us-east-2.amazonaws.com/dashboards/sprint-10/sprint-10-2021-07-26-x10959-dimer-neutral-restrained/retrospective_microstate_transformations/index.html
All code and scripts developed for this project are available onine, and all dashboards and calculations will be indexed here shortly:
https://github.com/foldingathome/covid-moonshot
This infrastructure will be reused to continue supporting the development of noval antivirals, producing large datasets on the accuracy of alchemical free energy calculations (to aid in their improvement) in the process.
Folding@home free energy calculation datasets:
All Folding@home datasets from this project are shared online through the AWS Public Dataset program, indexed here:
https://registry.opendata.aws/foldingathome-covid19/
Further work
Analysis of the wealth of data generated by this project is still ongoing, and will be disseminated via preprints and public code and dataset repositories in the coming months.
Last Modified: 10/31/2021
Modified by: John D Chodera
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