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Twenty years on: the impact of fragments on drug discovery
Abstract
After 20 years of sometimes quiet growth, fragment-based drug discovery (FBDD) has become mainstream. More than 30 drug candidates derived from fragments have entered the clinic, with two approved and several more in advanced trials. FBDD has been widely applied in both academia and industry, as evidenced by the large number of papers from universities, non-profit research institutions, biotechnology companies and pharmaceutical companies. Moreover, FBDD draws on a diverse range of disciplines, from biochemistry and biophysics to computational and medicinal chemistry. As the promise of FBDD strategies becomes increasingly realized, now is an opportune time to draw lessons and point the way to the future. This Review briefly discusses how to design fragment libraries, how to select screening techniques and how to make the most of information gleaned from them. It also shows how concepts from FBDD have permeated and enhanced drug discovery efforts.
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“Fragment-based ligand discovery (FBLD) has emerged as a versatile approach for the discovery of atom-efficient, small-molecule binders for a wide range of proteins10–12.”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [12]
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“and the hits can be achieved from following strategies such as high throughput screening (HTS) [15], fragment identification [16,17], structure-based drug design [18–20], artificial intelligence-based drug design [21], known compounds from the published literature [22], the repurposing of approved drugs [10,23] and DN…”
BackgroundInfluentialA generative deep learning approach to de novo antibiotic design
Krishnan, A., Anahtar, M. N., Valeri, J. A., Jin, W., Donghia, N. M., Sieben, L., Luttens, A., Zhang, Y., Modaresi, S. M., Hennes, A. D., et al. (2025) · Cell · doi:10.1016/j.cell.2025.07.033 · Cited by 119
Liu, Z., Tian, B., Chen, H., Wang, P., Brasier, A. R., & Zhou, J. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.04.006 · Cited by 104
The Time and Place for Nature in Drug Discovery
Young, R. J., Flitsch, S. L., Grigalunas, M., Leeson, P. D., Quinn, R. J., Turner, N. J., & Waldmann, H. (2022) · JACS Au · doi:10.1021/jacsau.2c00415 · Cited by 107
A general fragment-based approach to identify and optimize bioactive ligands targeting RNA
Suresh, B. M., Li, W., Zhang, P., Wang, K. W., Yildirim, I., Parker, C. G., & Disney, M. D. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2012217117 · Cited by 103
“Compared with conventional ligand discovery screens that use libraries of higher molecular weight compounds, fragment-based ligand discovery (FBLD) uses libraries of lower molecular weight compounds to more efficiently explore chemical space (13 – 15).”
Crystallographic screening using ultra-low-molecular-weight ligands to guide drug design
O’Reilly, M., Cleasby, A., Davies, T. G., Hall, R. J., Ludlow, R. F., Murray, C. W., Tisi, D., & Jhoti, H. (2019) · Drug Discovery Today · doi:10.1016/j.drudis.2019.03.009 · Cited by 100
Self-citationUbiquitin–proteasome system and the role of its inhibitors in cancer therapy
Aliabadi, F., Sohrabi, B., Mostafavi, E., Pazoki–Toroudi, H., & Webster, T. J. (2021) · Open Biology · doi:10.1098/rsob.200390 · Cited by 100
Large-scale chemoproteomics expedites ligand discovery and predicts ligand behavior in cells
Offensperger, F., Tin, G., Duran‐Frigola, M., Hahn, E., Dobner, S., Ende, C. W. A., Strohbach, J. W., Rukavina, A., Brennsteiner, V., Ogilvie, K., et al. (2024) · Science · doi:10.1126/science.adk5864 · Cited by 97
“Given the low affinity of fragment hits, FBLD has, until recently, been confined to in vitro setups ( 10 ).”
BackgroundDirecting evolution: the next revolution in drug discovery?
Davis, A. M., Plowright, A. T., & Valeur, E. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.146 · Cited by 88
Future challenges with DNA-encoded chemical libraries in the drug discovery domain
Zhao, G., Huang, Y., Zhou, Y., Li, Y., & Li, X. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1614559 · Cited by 86
A Strategy to Aminate Pyridines, Diazines, and Pharmaceuticals via Heterocyclic Phosphonium Salts
Patel, C., Mohnike, M., Hilton, M. C., & McNally, A. (2018) · Organic Letters · doi:10.1021/acs.orglett.8b00813 · Cited by 86
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Current perspectives and trend of computer-aided drug design: a review and bibliometric analysis
Wu, Z., Chen, S., Wang, Y., Li, F., Xu, H., Li, M., Zeng, Y., Wu, Z., & Gao, Y. (2024) · International Journal of Surgery · doi:10.1097/js9.0000000000001289 · Cited by 92
High-Throughput Screening for the Discovery of Enzyme Inhibitors
Lloyd, M. D. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00523 · Cited by 84
Theillet, F., & Luchinat, E. (2022) · Progress in Nuclear Magnetic Resonance Spectroscopy · doi:10.1016/j.pnmrs.2022.04.002 · Cited by 88
Fragment-Based Drug Design: From Then until Now, and Toward the Future
Xu, W., & Kang, C. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c00424 · Cited by 80
Evolution of commercially available compounds for HTS
Volochnyuk, D. M., Ryabukhin, S. V., Moroz, Y. S., Savych, O., Chuprina, A., Horvath, D., Zabolotna, Y., Varnek, A. A., & Judd, D. B. (2018) · Drug Discovery Today · doi:10.1016/j.drudis.2018.10.016 · Cited by 84
The rise of molecular simulations in fragment-based drug design (FBDD): an overview
Bissaro, M., Sturlese, M., & Moro, S. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.06.023 · Cited by 81
“Despite the smaller dimension differentiating the fragment-like chemical space from the drug-sized one, a canonical FBDD campaign in which a few thousand compounds are screened provides better coverage of the chemical diversity compared with a canonical HTS [9].”
Targeting the MAPK Pathway in RAS Mutant CancersPreprint
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“Vemurafenib was derived from a fragment-based drug discovery approach and, along with the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax, are examples of this approach leading to approved therapeutics (Erlanson et al. 2016).”
MethodStructure-based virtual screening of vast chemical space as a starting point for drug discovery
Carlsson, J., & Luttens, A. (2024) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2024.102829 · Cited by 88
“The intrinsically lower molecular complexity of fragments increases their likelihood to complement a binding site, giving rise to relatively high hit rates in experimental screens [47].”
BackgroundFragment-to-Lead Medicinal Chemistry Publications in 2018
Erlanson, D. A., de Esch, I. J. P., Jahnke, W., Johnson, C. N., & Mortenson, P. N. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01581 · Cited by 77
Self-citationFragment-based drug discovery: opportunities for organic synthesis
Denis, J. D. S., Hall, R. J., Murray, C. W., Heightman, T. D., & Rees, D. C. (2020) · RSC Medicinal Chemistry · doi:10.1039/d0md00375a · Cited by 77
Metadata
- Authors
- Erlanson, D. A., Fesik, S. W., Hubbard, R. E., Jahnke, W., & Jhoti, H.
- Affiliations
- Carmot Therapeutics (United States) (US)
- Vanderbilt University (US)
- Vernalis (R&D) Limited (United Kingdom) (GB)
- Novartis (Switzerland) (CH)
- Corresponding author
- Erlanson, Daniel A.
- Venue
- Nature Reviews Drug Discovery
- Published
- 2016-07-15
- Volume
- 15
- Issue
- 9
- Pages
- 605-619
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- OpenAlex
- W2467779447
- Cited by
- 1,000
- References
- 110
- Citations by year
- 2026: 80 · 2025: 92 · 2024: 112 · 2023: 95 · 2022: 97 · 2021: 106 · 2020: 141 · 2019: 79 · 2018: 99 · 2017: 84 · 2016: 14
- FWCI
- 7.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- fragment-based drug discovery, fragment libraries, fragment screening
- MeSH terms
- Clinical Trials as Topic, Humans, Peptide Fragments, Protein Conformation, Peptide Library, Computational Biology, Small Molecule Libraries, Drug Discovery, High-Throughput Screening Assays
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