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The Design of Covalent Allosteric Drugs

Nussinov, Ruth, Tsai, Chung-Jung·2015·Annual Review of Pharmacology and Toxicology

DOI 10.1146/annurev-pharmtox-010814-124401

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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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Authors: Nussinov, R., & Tsai, C.-J.
Affiliations: Tel Aviv University (IL)
Frederick National Laboratory for Cancer Research (US)
ORCID: Nussinov, Ruth
Tsai, Chung-Jung
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
DOI: 10.1146/annurev-pharmtox-010814-124401
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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The Design of Covalent Allosteric Drugs

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