Fragment Binding to the Nsp3 Macrodomain of SARS-CoV-2 Identified Through Crystallographic Screening and Computational Docking.

Autor: Schuller M; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK., Correy GJ; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA., Gahbauer S; Department of Pharmaceutical Chemistry, University of California San Francisco San Francisco, CA, USA., Fearon D; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom., Wu T; Institute for Neurodegenerative Disease, University of California San Francisco, CA, USA.; Chemistry and Chemical Biology Graduate Program, University of California San Francisco, CA, USA., Díaz RE; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA.; Tetrad Graduate Program, University of California San Francisco, CA, USA., Young ID; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA.; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA., Martins LC; Biochemistry Department, Institute for Biological Sciences, Federal University of Minas Gerais. Belo Horizonte, Brazil., Smith DH; Helen Diller Family Comprehensive Cancer, University of California San Francisco, CA, USA., Schulze-Gahmen U; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA., Owens TW; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA., Deshpande I; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA., Merz GE; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA., Thwin AC; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA., Biel JT; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA., Peters JK; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA., Moritz M; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA., Herrera N; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA., Kratochvil HT; Quantitative Biosciences Institute (QBI) Coronavirus Research Group Structural Biology Consortium, University of California San Francisco, CA, USA., Aimon A; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom., Bennett JM; Centre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK., Neto JB; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom., Cohen AE; Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA., Dias A; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom., Douangamath A; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom., Dunnett L; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom., Fedorov O; Centre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK., Ferla MP; Wellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK., Fuchs M; National Synchrotron Light Source II, Brookhaven National Laboratory, Upton, NY, USA., Gorrie-Stone TJ; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom., Holton JM; Department of Biochemistry and Biophysics, University of California San Francisco, CA, USA.; Department of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.; Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA., Johnson MG; ChemPartner Corporation, South San Francisco, CA, USA., Krojer T; Centre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK.; Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, UK., Meigs G; Department of Biochemistry and Biophysics, University of California San Francisco, CA, USA.; Department of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Powell AJ; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom., Rangel VL; Centre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK.; Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, UK.; School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, São Paulo, Brazil., Russi S; Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA., Skyner RE; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom., Smith CA; Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA., Soares AS; Photon Sciences, Brookhaven National Laboratory, Upton, NY, USA., Wierman JL; Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Center, Menlo Park, CA 94025, USA., Zhu K; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK., Jura N; Department of Cellular and Molecular Pharmacology, University of California San Francisco, CA, USA., Ashworth A; Helen Diller Family Comprehensive Cancer, University of California San Francisco, CA, USA., Irwin J; Department of Pharmaceutical Chemistry, University of California San Francisco San Francisco, CA, USA., Thompson MC; Department of Chemistry and Chemical Biology, University of California Merced, CA, USA., Gestwicki JE; Department of Pharmaceutical Chemistry, University of California San Francisco San Francisco, CA, USA.; Institute for Neurodegenerative Disease, University of California San Francisco, CA, USA., von Delft F; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, United Kingdom.; Centre for Medicines Discovery, University of Oxford, South Parks Road, Headington, OX3 7DQ, UK.; Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, UK.; Department of Biochemistry, University of Johannesburg, Auckland Park, 2006, South Africa., Shoichet BK; Department of Pharmaceutical Chemistry, University of California San Francisco San Francisco, CA, USA., Fraser JS; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA., Ahel I; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2020 Nov 24. Date of Electronic Publication: 2020 Nov 24.
DOI: 10.1101/2020.11.24.393405
Abstrakt: The SARS-CoV-2 macrodomain (Mac1) within the non-structural protein 3 (Nsp3) counteracts host-mediated antiviral ADP-ribosylation signalling. This enzyme is a promising antiviral target because catalytic mutations render viruses non-pathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of diverse fragment libraries resulted in 214 unique macrodomain-binding fragments, out of 2,683 screened. An additional 60 molecules were selected from docking over 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several crystallographic and docking fragment hits were validated for solution binding using three biophysical techniques (DSF, HTRF, ITC). Overall, the 234 fragment structures presented explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.
Databáze: MEDLINE