Cited by 401Computational Drug Discovery MethodsChemical Synthesis and AnalysisEnzyme Structure and Function

Tethering: Fragment-Based Drug Discovery

Erlanson, Daniel A., Wells, James A., Braisted, Andrew C.·2004·Annual Review of Biophysics and Biomolecular Structure

Abstract

▪ Abstract The genomics revolution has provided a deluge of new targets for drug discovery. To facilitate the drug discovery process, many researchers are turning to fragment-based approaches to find lead molecules more efficiently. One such method, Tethering 1 , allows for the identification of small-molecule fragments that bind to specific regions of a protein target. These fragments can then be elaborated, combined with other molecules, or combined with one another to provide high-affinity drug leads. In this review we describe the background and theory behind Tethering and discuss its use in identifying novel inhibitors for protein targets including interleukin-2 (IL-2), thymidylate synthase (TS), protein tyrosine phosphatase 1B (PTP-1B), and caspases.

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Crossref · 10.1146/annurev.biophys.33.110502.140409

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  • Compound 12, the first mutant-selective covalent KRAS(G12C) inhibitor, was found by tethering 480 disulfide fragments against GDP-bound KRAS(G12C).

    “The inhibitor (compound 12 in their study) was discovered through a disulfide-fragment screening approach known as tethering, whereby a library of 480 disulfide fragments was screened against KRAS(G12C) in the GDP-bound state using intact protein mass spectrometry (MS)88,90.”

    From Advances in covalent drug discovery (2022) · cites this paper as [90]

  • Tethering uses libraries of compounds linked to disulfides to identify fragments that bind cysteine-adjacent pockets.

    “Originally, MS-based compound screening grew out of ‘tethering’, which is a technique employed since 2000 that uses libraries of compounds linked to disulfides to identify fragments that bind cysteine-adjacent pockets90,147.”

    From Advances in covalent drug discovery (2022) · cites this paper as [90]

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Authors
Erlanson, D. A., Wells, J. A., & Braisted, A. C.
Affiliations
Sunesis (United States) (US)
Venue
Annual Review of Biophysics and Biomolecular Structure
Published
2004-06-09
Volume
33
Issue
1
Pages
199-223
ISSN
  • 1056-8700 (ISSN-L)
  • 1545-4266
OpenAlex
W2138958920
Cited by
385
References
78
Citations by year
2026: 5 · 2025: 7 · 2024: 17 · 2023: 16 · 2022: 17 · 2021: 8 · 2020: 17 · 2019: 17 · 2018: 21 · 2017: 6 · 2016: 18 · 2015: 21 · 2014: 23 · 2013: 11 · 2012: 29
FWCI
1.77
Type
journal article
Language
en
Open access
closed
Locations
  • Annual Review of Biophysics and Biomolecular Structure (publishedVersion)
  • PubMed (publishedVersion)
Funders
Sunesis
Topics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords
tethering, fragment-based drug discovery, small-molecule fragments, protein-ligand binding, lead compound identification, interleukin-2, thymidylate synthase, PTP1B, caspases, protein inhibitors
MeSH terms
Binding Sites, Peptide Fragments, Protein Binding, Proteins, Drug Design, Protein Interaction Mapping, Protein Array Analysis

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