Tethering: Fragment-Based Drug Discovery
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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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
- Publisher
- Annual Reviews
- 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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