AI-Accelerated Design of Targeted Covalent Inhibitors for SARS-CoV-2
- Rajendra P. JoshiRajendra P. JoshiEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington 99352, United StatesMore by Rajendra P. Joshi
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- Katherine J. SchultzKatherine J. SchultzEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington 99352, United StatesMore by Katherine J. Schultz
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- Jesse William WilsonJesse William WilsonEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington 99352, United StatesMore by Jesse William Wilson
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- Agustin KruelAgustin KruelEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington 99352, United StatesMore by Agustin Kruel
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- Rohith Anand VarikotiRohith Anand VarikotiEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington 99352, United StatesMore by Rohith Anand Varikoti
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- Chathuri J. KombalaChathuri J. KombalaElson S. Floyd College of Medicine, Department of Nutrition and Exercise Physiology, Washington State University, Spokane, Washington 99202, United StatesMore by Chathuri J. Kombala
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- Daniel W. KnellerDaniel W. KnellerNeutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesNational Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United StatesMore by Daniel W. Kneller
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- Stephanie GalanieStephanie GalanieNational Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United StatesBiosciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesDepartment of Process Research and Development, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065, United StatesMore by Stephanie Galanie
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- Gwyndalyn PhillipsGwyndalyn PhillipsNeutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesNational Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United StatesMore by Gwyndalyn Phillips
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- Qiu ZhangQiu ZhangNeutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesNational Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United StatesMore by Qiu Zhang
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- Leighton CoatesLeighton CoatesNational Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United StatesSecond Target Station, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesMore by Leighton Coates
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- Jyothi ParvathareddyJyothi ParvathareddyRegional Biocontainment Laboratory, The University of Tennessee Health Science Center, Memphis, Tennessee 38105, United StatesMore by Jyothi Parvathareddy
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- Surekha SurendranathanSurekha SurendranathanRegional Biocontainment Laboratory, The University of Tennessee Health Science Center, Memphis, Tennessee 38105, United StatesMore by Surekha Surendranathan
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- Ying KongYing KongRegional Biocontainment Laboratory, The University of Tennessee Health Science Center, Memphis, Tennessee 38105, United StatesMore by Ying Kong
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- Austin ClydeAustin ClydeNational Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United StatesData Science and Learning Division, Argonne National Laboratory, Lemont, Illinois 60439, United StatesMore by Austin Clyde
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- Arvind RamanathanArvind RamanathanNational Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United StatesData Science and Learning Division, Argonne National Laboratory, Lemont, Illinois 60439, United StatesMore by Arvind Ramanathan
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- Colleen B. JonssonColleen B. JonssonRegional Biocontainment Laboratory, The University of Tennessee Health Science Center, Memphis, Tennessee 38105, United StatesInstitute for the Study of Host-Pathogen Systems, University of Tennessee Health Science Center, Memphis, Tennessee 38103, United StatesDepartment of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 38103, United StatesMore by Colleen B. Jonsson
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- Kristoffer R. BrandvoldKristoffer R. BrandvoldEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington 99352, United StatesElson S. Floyd College of Medicine, Department of Nutrition and Exercise Physiology, Washington State University, Spokane, Washington 99202, United StatesMore by Kristoffer R. Brandvold
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- Mowei ZhouMowei ZhouEarth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington 99352, United StatesNational Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United StatesMore by Mowei Zhou
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- Martha S. Head*Martha S. Head*Email: [email protected]National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United StatesJoint Institute for Biological Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesCenter for Research Acceleration by Digital Innovation, Amgen Research, Thousand Oaks, California 91320, United StatesMore by Martha S. Head
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- Andrey Kovalevsky*Andrey Kovalevsky*Email: [email protected]Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United StatesNational Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United StatesMore by Andrey Kovalevsky
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- Neeraj Kumar*Neeraj Kumar*Email: [email protected]Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington 99352, United StatesNational Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United StatesMore by Neeraj Kumar
Abstract
Direct-acting antivirals for the treatment of the COVID-19 pandemic caused by the SARS-CoV-2 virus are needed to complement vaccination efforts. Given the ongoing emergence of new variants, automated experimentation, and active learning based fast workflows for antiviral lead discovery remain critical to our ability to address the pandemic’s evolution in a timely manner. While several such pipelines have been introduced to discover candidates with noncovalent interactions with the main protease (Mpro), here we developed a closed-loop artificial intelligence pipeline to design electrophilic warhead-based covalent candidates. This work introduces a deep learning-assisted automated computational workflow to introduce linkers and an electrophilic “warhead” to design covalent candidates and incorporates cutting-edge experimental techniques for validation. Using this process, promising candidates in the library were screened, and several potential hits were identified and tested experimentally using native mass spectrometry and fluorescence resonance energy transfer (FRET)-based screening assays. We identified four chloroacetamide-based covalent inhibitors of Mpro with micromolar affinities (KI of 5.27 μM) using our pipeline. Experimentally resolved binding modes for each compound were determined using room-temperature X-ray crystallography, which is consistent with the predicted poses. The induced conformational changes based on molecular dynamics simulations further suggest that the dynamics may be an important factor to further improve selectivity, thereby effectively lowering KI and reducing toxicity. These results demonstrate the utility of our modular and data-driven approach for potent and selective covalent inhibitor discovery and provide a platform to apply it to other emerging targets.
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This article is cited by 1 publications.
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