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

Autor: Gahbauer S; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA., Correy GJ; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA., Schuller M; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK., Ferla MP; Wellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK.; National Institute for Health Research Oxford Biomedical Research Centre, Oxford, OX4 2PG, UK., Doruk YU; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA., Rachman M; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA., Wu T; Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA 94158, USA.; Chemistry and Chemical Biology Graduate Program, University of California San Francisco, San Francisco, CA 94158, USA., Diolaiti M; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA., Wang S; Chemistry and Chemical Biology Graduate Program, University of California San Francisco, San Francisco, CA 94158, USA., Neitz RJ; Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, California 94158, USA., Fearon D; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK.; Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK., Radchenko D; Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine.; Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv, 01601, Ukraine., Moroz Y; Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv, 01601, Ukraine.; Chemspace, Chervonotkatska Street 78, Kyiv, 02094, Ukraine., Irwin JJ; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA., Renslo AR; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.; Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, California 94158, USA., Taylor JC; Wellcome Centre for Human Genetics, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK.; National Institute for Health Research Oxford Biomedical Research Centre, Oxford, OX4 2PG, UK., Gestwicki JE; Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA 94158, USA.; Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, California 94158, USA., von Delft F; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK.; Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, UK.; 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., Ashworth A; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA., Ahel I; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK., Shoichet BK; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA., Fraser JS; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2022 Jul 28. Date of Electronic Publication: 2022 Jul 28.
DOI: 10.1101/2022.06.27.497816
Abstrakt: 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 in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 152 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated protein dynamics within the active site, and key inhibitor motifs that will template future drug development against Mac1.
Databáze: MEDLINE