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Structural Biology and Drug Discovery of Difficult Targets: The Limits of Ligandability
Open accessAbstract
Over the past decade, researchers in the pharmaceutical industry and academia have made retrospective analyses of successful drug campaigns in order to establish "rules" to guide the selection of new target proteins. They have identified features that are considered undesirable and some that make targets "unligandable." This review focuses on the factors that make targets difficult: featureless binding sites, the lack of hydrogen-bond donors and acceptors, the presence of metal ions, the need for adaptive changes in conformation, and the lipophilicity of residues at the protein-ligand interface. Protein-protein interfaces of multiprotein assemblies share many of these undesirable features, although those that involve concerted binding and folding in their assembly have better defined pockets or grooves, and these can provide opportunities for identifying hits and for lead optimization. In some protein-protein interfaces conformational changes-often involving rearrangement of large side chains such as those of tyrosine, tryptophan, or arginine-are required to configure an appropriate binding site, and this may require tethering of the ligands until higher affinity is achieved. In many enzymes, larger conformational rearrangements are required to form the binding site, and these can make fragment-based approaches particularly difficult.
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“not all members of a protein family have drug-compatible or ligandable21 binding sites”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [21]
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Metadata
- Authors
- Surade, S., & Blundell, T. L.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Blundell, Tom L.
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 19
- Issue
- 1
- Pages
- 42-50
- ISSN
- 1074-5521 (ISSN-L)
- OpenAlex
- W2084501039
- Cited by
- 230
- References
- 97
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 15 · 2023: 10 · 2022: 12 · 2021: 18 · 2020: 10 · 2019: 9 · 2018: 16 · 2017: 20 · 2016: 31 · 2015: 19 · 2014: 11 · 2013: 22 · 2012: 12
- FWCI
- 2.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Chemistry & Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bill and Melinda Gates Foundation
- University of Pittsburgh
- Wellcome Trust
- European Commission
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- ligandability, target selection, protein binding sites, hydrogen bond donors and acceptors, protein conformational change, protein-protein interfaces, fragment-based drug discovery, lead optimization
- MeSH terms
- Binding Sites, Ligands, Proteins, Catalytic Domain, BRCA2 Protein, Protein Interaction Mapping, Rad51 Recombinase, Drug Discovery
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