The design of covalent allosteric drugs

Ruth Nussinov, Chung Jung Tsai

Research output: Contribution to journalReview articlepeer-review


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.

Original languageEnglish
Pages (from-to)249-267
Number of pages19
JournalAnnual Review of Pharmacology and Toxicology
StatePublished - 6 Jan 2015


  • Agonist
  • Allosteric drug discovery
  • Allosteric modulator
  • Antagonist
  • Pharmacology
  • Toxicity


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