The DOI matches its Crossref record; 105 of the 105 references it cites were found in a registry or an index.
The Design of Covalent Allosteric Drugs
Abstract
A key issue in drug discovery is how to reduce drug dosage and increase specificity while retaining or increasing efficacy, as high dosage is often linked to toxicity. There are two types of drugs on the market: orthosteric and allosteric. Orthosteric drugs can be noncovalent or covalent. The latter are advantageous because they may be prescribed in lower doses, but their potential off-target toxicity is a primary concern. The chief advantages of allosteric drugs are their higher specificity and their consequently lower chance of toxic side effects. Covalent allosteric drugs combine the pharmacological merits of covalent drugs with the additional benefit of the higher specificity of allosteric drugs. In a recent promising step in therapeutic drug development, allosteric, disulfide-tethered fragments successfully modulated the activity of a protein kinase and K-Ras.
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“Due to its higher specificity and consequently lower toxicity, which results from targeting nonconserved allosteric sites, allostery also increasingly features in allosteric drugs.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [120]
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Metadata
- Authors
- Nussinov, R., & Tsai, C.-J.
- Affiliations
- Tel Aviv University (IL)
- Frederick National Laboratory for Cancer Research (US)
- Venue
- Annual Review of Pharmacology and Toxicology
- Publisher
- Annual Reviews
- Published
- 2015-01-06
- Volume
- 55
- Issue
- 1
- Pages
- 249-267
- ISSN
- 0362-1642 (ISSN-L)
- 1545-4304
- OpenAlex
- W2101700924
- Cited by
- 112
- References
- 105
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 6 · 2023: 8 · 2022: 10 · 2021: 15 · 2020: 10 · 2019: 11 · 2018: 5 · 2017: 10 · 2016: 15 · 2015: 10
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Annual Review of Pharmacology and Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (HHSN261200800001E)
- National Cancer Institute
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- allosteric drug design, drug specificity, off-target toxicity, KRAS, drug dosage reduction
- MeSH terms
- Allosteric Regulation, Animals, Binding Sites, Enzyme Inhibitors, Humans, Kinetics, Models, Molecular, Protein Binding, Protein Conformation, Structure-Activity Relationship, Drug Design, Molecular Structure, Signal Transduction, Computer-Aided Design, Enzyme Activators, Drug-Related Side Effects and Adverse Reactions
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