Evidence map›Paper›PMID 35794891›Full record

ArticlebioRxiv : the preprint server for biology2022

Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 Macrodomain of SARS-CoV-2.

Stefan Gahbauer, Galen J Correy, Marion Schuller, Matteo P Ferla, Yagmur Umay Doruk, Moira Rachman, Taiasean Wu, Morgan Diolaiti, Siyi Wang, R Jeffrey Neitz and 12 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

22 authors.

Stefan GahbauerDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
Galen J CorreyDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.
Marion SchullerSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK.
Matteo P FerlaWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK.
Yagmur Umay DorukHelen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.
Moira RachmanDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
Taiasean WuInstitute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA 94158, USA.
Morgan DiolaitiHelen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.
Siyi WangChemistry and Chemical Biology Graduate Program, University of California San Francisco, San Francisco, CA 94158, USA.
R Jeffrey NeitzDepartment of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, California 94158, USA.
Daren FearonDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK.
Dmytro RadchenkoEnamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine.
Yurii MorozTaras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv, 01601, Ukraine.
John J IrwinDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
Adam R RensloHelen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.
Jenny C TaylorWellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK.
Jason E GestwickiInstitute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA 94158, USA.
Frank von DelftDiamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK.
Alan AshworthHelen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.
Ivan AhelSir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK.
Brian K ShoichetDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
James S FraserDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.

Funding

Targeting Viroporins and Coronavirus M ProteinU19AI171110 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Nevan J Krogan · 2022 to 2026
$103.4M
A Synchrotron Radiation Structural Biology ResourcesP30GM133894 · NIGMS · STANFORD UNIVERSITY · PI Ritimukta Sarangi · 2020 to 2026
$43.3M
X-ray Scattering Technology CoreP30GM133893 · NIGMS · BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB · PI Sean McSweeney · 2019 to 2026
$38.6M
User Training and OutreachP30GM124169 · NIGMS · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI PAUL David ADAMS, Gregory L Hura · 2017 to 2026
$28.6M
Development and Testing of New Computational Methods for Ligand Discovery and MechanismR35GM122481 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Brian K Shoichet · 2017 to 2026
$8.5M
A Web-Based Automatic Virtual Screening SystemR01GM071896 · NIGMS · UNIVERSITY OF TORONTO · PI IRWIN, JOHN J. · 2004 to 2024
$6.0M
Ultra-large library docking for ligand discoveryR01GM133836 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI IRWIN, JOHN J. · 2019 to 2022
$1.6M
Differential Scanning Fluorimetry (DSF) Methods for Studying Protein StabilityR01GM141299 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GESTWICKI, JASON E · 2021 to 2024
$1.5M
Cancer Research UK 22284NIAID NIH HHS U19 AI171110NIGMS NIH HHS P30 GM124169NIGMS NIH HHS P30 GM133893NIGMS NIH HHS P30 GM133894NIGMS NIH HHS R01 GM071896NIGMS NIH HHS R01 GM133836NIGMS NIH HHS R01 GM141299NIGMS NIH HHS R35 GM122481Wellcome Trust 210634/Z/18/Z
6 · The paper itself

Abstract

The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with

Indexed as

coronavirusfragment-based drug discoveryNsp3 macrodomainvirtual screening

Identifiers

PMID35794891
PMCPMC9258288

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.