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An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mpro inhibitor

Daniel Zaidman, Paul Gehrtz, Mihajlo Filep, Daren Fearon, Jaime Prilusky, Shirly Duberstein, Galit Cohen, David Owen, Efrat Resnick, Claire Strain-Damerell, Petra Lukacik, Covid-Moonshot Consortium, Haim Barr, Martin A. Walsh, View ORCID ProfileFrank von Delft, View ORCID ProfileNir London
doi: https://doi.org/10.1101/2020.09.21.299776
Daniel Zaidman
1Dept. of Organic Chemistry, Weizmann Institute of Science, 7610001, Rehovot, Israel
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Paul Gehrtz
1Dept. of Organic Chemistry, Weizmann Institute of Science, 7610001, Rehovot, Israel
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Mihajlo Filep
1Dept. of Organic Chemistry, Weizmann Institute of Science, 7610001, Rehovot, Israel
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Daren Fearon
2Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0QX, U.K
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Jaime Prilusky
3Life Sciences Core Facilities, Weizmann Institute of Science, 7610001, Rehovot, Israel
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Shirly Duberstein
4Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot, 7610001, Israel
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Galit Cohen
4Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot, 7610001, Israel
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David Owen
2Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0QX, U.K
5Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, U.K
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Efrat Resnick
1Dept. of Organic Chemistry, Weizmann Institute of Science, 7610001, Rehovot, Israel
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Claire Strain-Damerell
2Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0QX, U.K
5Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, U.K
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Petra Lukacik
2Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0QX, U.K
5Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, U.K
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Haim Barr
4Wohl Institute for Drug Discovery of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot, 7610001, Israel
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Martin A. Walsh
2Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0QX, U.K
5Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, U.K
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Frank von Delft
2Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0QX, U.K
5Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, U.K
6Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, OX3 7DQ, UK
7Department of Biochemistry, University of Johannesburg, Auckland Park 2006, South Africa
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  • ORCID record for Frank von Delft
Nir London
1Dept. of Organic Chemistry, Weizmann Institute of Science, 7610001, Rehovot, Israel
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  • For correspondence: nir.london@weizmann.ac.il
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Abstract

Designing covalent inhibitors is a task of increasing importance in drug discovery. Efficiently designing irreversible inhibitors, though, remains challenging. Here, we present covalentizer, a computational pipeline for creating irreversible inhibitors based on complex structures of targets with known reversible binders. For each ligand, we create a custom-made focused library of covalent analogs. We use covalent docking, to dock these tailored covalent libraries and to find those that can bind covalently to a nearby cysteine while keeping some of the main interactions of the original molecule. We found ~11,000 cysteines in close proximity to a ligand across 8,386 protein-ligand complexes in the PDB. Of these, the protocol identified 1,553 structures with covalent predictions. In prospective evaluation against a panel of kinases, five out of nine predicted covalent inhibitors showed IC50 between 155 nM - 4.2 μM. Application of the protocol to an existing SARS-CoV-1 Mpro reversible inhibitor led to a new acrylamide inhibitor series with low micromolar IC50 against SARS-CoV-2 Mpro. The docking prediction was validated by 11 co-crystal structures. This is a promising lead series for COVID-19 antivirals. Together these examples hint at the vast number of covalent inhibitors accessible through our protocol.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://covalentizer.weizmann.ac.il/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 22, 2020.
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An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mpro inhibitor
Daniel Zaidman, Paul Gehrtz, Mihajlo Filep, Daren Fearon, Jaime Prilusky, Shirly Duberstein, Galit Cohen, David Owen, Efrat Resnick, Claire Strain-Damerell, Petra Lukacik, Covid-Moonshot Consortium, Haim Barr, Martin A. Walsh, Frank von Delft, Nir London
bioRxiv 2020.09.21.299776; doi: https://doi.org/10.1101/2020.09.21.299776
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An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mpro inhibitor
Daniel Zaidman, Paul Gehrtz, Mihajlo Filep, Daren Fearon, Jaime Prilusky, Shirly Duberstein, Galit Cohen, David Owen, Efrat Resnick, Claire Strain-Damerell, Petra Lukacik, Covid-Moonshot Consortium, Haim Barr, Martin A. Walsh, Frank von Delft, Nir London
bioRxiv 2020.09.21.299776; doi: https://doi.org/10.1101/2020.09.21.299776

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