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

Gahbauer S, Correy GJ, Schuller M, Ferla MP, Doruk YU, Rachman M, Wu T, Diolaiti M, Wang S, Neitz RJ, Fearon D, Radchenko DS, Moroz YS, Irwin JJ, Renslo AR, Taylor JC, Gestwicki JE, von Delft F, Ashworth A, Ahel I, Shoichet BK, Fraser JS
Proc Natl Acad Sci U S A 120 e2212931120 (2023)
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Cited: 16 times
EuropePMC logo PMID: 36598939

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.

Articles - 5sqi mentioned but not cited (2)

  1. Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2. Gahbauer S, Correy GJ, Schuller M, Ferla MP, Doruk YU, Rachman M, Wu T, Diolaiti M, Wang S, Neitz RJ, Fearon D, Radchenko DS, Moroz YS, Irwin JJ, Renslo AR, Taylor JC, Gestwicki JE, von Delft F, Ashworth A, Ahel I, Shoichet BK, Fraser JS. Proc Natl Acad Sci U S A 120 e2212931120 (2023)
  2. research-article Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 Macrodomain of SARS-CoV-2. Gahbauer S, Correy GJ, Schuller M, Ferla MP, Doruk YU, Rachman M, Wu T, Diolaiti M, Wang S, Neitz RJ, Fearon D, Radchenko D, Moroz Y, Irwin JJ, Renslo AR, Taylor JC, Gestwicki JE, von Delft F, Ashworth A, Ahel I, Shoichet BK, Fraser JS. bioRxiv 2022.06.27.497816 (2022)


Reviews citing this publication (5)

  1. Computational approaches streamlining drug discovery. Sadybekov AV, Katritch V. Nature 616 673-685 (2023)
  2. PARPs and ADP-ribosylation: Deciphering the complexity with molecular tools. Dasovich M, Leung AKL. Mol Cell 83 1552-1572 (2023)
  3. Accelerating antiviral drug discovery: lessons from COVID-19. von Delft A, Hall MD, Kwong AD, Purcell LA, Saikatendu KS, Schmitz U, Tallarico JA, Lee AA. Nat Rev Drug Discov 22 585-603 (2023)
  4. An Update on the Current State of SARS-CoV-2 Mac1 Inhibitors. O'Connor JJ, Ferraris D, Fehr AR. Pathogens 12 1221 (2023)
  5. Fluorine-a small magic bullet atom in the drug development: perspective to FDA approved and COVID-19 recommended drugs. Chandra G, Singh DV, Mahato GK, Patel S. Chem Zvesti 1-22 (2023)

Articles citing this publication (9)

  1. Room-temperature crystallography reveals altered binding of small-molecule fragments to PTP1B. Skaist Mehlman T, Biel JT, Azeem SM, Nelson ER, Hossain S, Dunnett L, Paterson NG, Douangamath A, Talon R, Axford D, Orins H, von Delft F, Keedy DA. Elife 12 e84632 (2023)
  2. Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors. Fink EA, Bardine C, Gahbauer S, Singh I, Detomasi TC, White K, Gu S, Wan X, Chen J, Ary B, Glenn I, O'Connell J, O'Donnell H, Fajtová P, Lyu J, Vigneron S, Young NJ, Kondratov IS, Alisoltani A, Simons LM, Lorenzo-Redondo R, Ozer EA, Hultquist JF, O'Donoghue AJ, Moroz YS, Taunton J, Renslo AR, Irwin JJ, García-Sastre A, Shoichet BK, Craik CS. Protein Sci 32 e4712 (2023)
  3. SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice. Alhammad YM, Parthasarathy S, Ghimire R, Kerr CM, O'Connor JJ, Pfannenstiel JJ, Chanda D, Miller CA, Baumlin N, Salathe M, Unckless RL, Zuñiga S, Enjuanes L, More S, Channappanavar R, Fehr AR. Proc Natl Acad Sci U S A 120 e2302083120 (2023)
  4. A single inactivating amino acid change in the SARS-CoV-2 NSP3 Mac1 domain attenuates viral replication in vivo. Taha TY, Suryawanshi RK, Chen IP, Correy GJ, McCavitt-Malvido M, O'Leary PC, Jogalekar MP, Diolaiti ME, Kimmerly GR, Tsou CL, Gascon R, Montano M, Martinez-Sobrido L, Krogan NJ, Ashworth A, Fraser JS, Ott M. PLoS Pathog 19 e1011614 (2023)
  5. PARP14 is a writer, reader, and eraser of mono-ADP-ribosylation. Torretta A, Chatzicharalampous C, Ebenwaldner C, Schüler H. J Biol Chem 299 105096 (2023)
  6. A Fluorescence Polarization Assay for Macrodomains Facilitates the Identification of Potent Inhibitors of the SARS-CoV-2 Macrodomain. Anmangandla A, Jana S, Peng K, Wallace SD, Bagde SR, Drown BS, Xu J, Hergenrother PJ, Fromme JC, Lin H. ACS Chem Biol 18 1200-1207 (2023)
  7. Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors. Schuller M, Zarganes-Tzitzikas T, Bennett J, De Cesco S, Fearon D, von Delft F, Fedorov O, Brennan PE, Ahel I. Pathogens 12 324 (2023)
  8. Protocol for performing and optimizing differential scanning fluorimetry experiments. Wu T, Hornsby M, Zhu L, Yu JC, Shokat KM, Gestwicki JE. STAR Protoc 4 102688 (2023)
  9. The DarT/DarG Toxin-Antitoxin ADP-Ribosylation System as a Novel Target for a Rational Design of Innovative Antimicrobial Strategies. Catara G, Caggiano R, Palazzo L. Pathogens 12 240 (2023)


Related citations provided by authors (1)

  1. Structure-based inhibitor optimization for the Nsp3 Macrodomain of SARS-CoV-2.. Gahbauer S, Correy GJ, Schuller M, Ferla MP, Doruk YU, Rachman M, Wu T, Diolaiti M, Wang S, Neitz RJ, Fearon D, Radchenko D, Moroz Y, Irwin JJ, Renslo AR, Taylor JC, Gestwicki JE, von Delft F, Ashworth A, Ahel I, Shoichet BK, Fraser JS bioRxiv (2022)

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