ArticleProceedings of the National Academy of Sciences of the United States of America2023
Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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Who cites it
87 citing papers in PubMed, 122 citations in OpenAlex.
- Article
- Docking-based virtual screening: Past, present, and future.Biophysical journal · 2026Review
- A resource-efficient structure-based workflow for fragment progression enables parallel hit discovery and validation of functionally diverse modulators of NCS-1 protein-protein interactions.Chemical science · 2026Article
- Cellular engagement of the SARS-CoV-2 macrodomain by GS-441524 and enhancedRSC chemical biology · 2026Article
- Design, structure-based optimization and antiviral evaluation of potent inhibitors for the macrodomain Mac1 of SARS-CoV-2.Nature communications · 2026Article
- X-ray Crystallography-Guided Design and Synthesis of Cyclopentyl Heteroaryl Carboxylic Acid-Based Inhibitors of the SARS-CoV-2 Nsp3 Macrodomain (Mac1).Journal of medicinal chemistry · 2026Article
- Emergence of specific binding and catalysis from a designed generalist binding protein.Nature chemistry · 2026Article
- Targeting SARS-CoV-2 Non-Structural Proteins: A Blueprint for Next-Generation Small-Molecule Coronavirus Antivirals.Pharmaceutics · 2026Review
- Structure, function, regulation, evolution, and therapeutic implications of PARP14.Genes & development · 2026Review
- The Selectivity Implications of Docking Libraries with Greater and Lesser Similarities to Bio-like Molecules.Journal of medicinal chemistry · 2026Article
- An Automated Workflow for Diagnosing Sampling Issues Caused by Slow Torsional Motions in Molecular Simulations.Journal of chemical information and modeling · 2026Article
- Interactomics of SARS-CoV-2 Macrodomain 1 Reveals Putative Clients of ADP-Ribosyl Hydrolase Activity.Viruses · 2026Article
- Synthesis and Biological Evaluation of Modified Peptide Derivatives Targeting the SARS-CoV‑2 Nsp3 Macrodomain (Mac1) Replication Domain.ACS omega · 2026Article
- Efficient Binding Affinity Estimation for Fragment-Based Compounds Using a Separated Topologies Approach.Journal of chemical information and modeling · 2026Article
- SARS-CoV-2 nonstructural protein 3 remodels the phosphorylation of target proteins via protein-protein interactions.Microbiology spectrum · 2026Article
- Screening assay to monitor mono-ADP-ribosylhydrolase activity of viral macrodomains in cells.Communications biology · 2026Article
- Antiviral drug discovery and development: challenges and future directions.Signal transduction and targeted therapy · 2026Review
- CACHE Challenge #3: Targeting the Nsp3 Macrodomain of SARS-CoV-2.Journal of chemical information and modeling · 2026Article
- The selectivity implications of docking libraries with greater and lesser similarities to bio-like molecules.bioRxiv : the preprint server for biology · 2026Article
- Discovery of AVI-6451, a Potent and Selective Inhibitor of the SARS-CoV-2 ADP-Ribosylhydrolase Mac1 with Oral Efficacy In Vivo.Journal of medicinal chemistry · 2026Article
27 more citing papers are in PubMed but not listed here.
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Authors and funding
22 authors at 6 institutions in 4 countries.
Funding
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 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 153 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 conformational changes within the active site, and key inhibitor motifs that will template future drug development against Mac1.
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Registered trials
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.