The design of covalent allosteric drugs

Annu Rev Pharmacol Toxicol. 2015:55:249-67. doi: 10.1146/annurev-pharmtox-010814-124401. Epub 2014 Aug 21.


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.

Keywords: agonist; allosteric drug discovery; allosteric modulator; antagonist; pharmacology; toxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Allosteric Regulation
  • Animals
  • Binding Sites
  • Computer-Aided Design
  • Drug Design*
  • Drug-Related Side Effects and Adverse Reactions / etiology
  • Drug-Related Side Effects and Adverse Reactions / prevention & control
  • Enzyme Activators / adverse effects
  • Enzyme Activators / chemistry
  • Enzyme Activators / pharmacology*
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Kinetics
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Protein Conformation
  • Signal Transduction / drug effects
  • Structure-Activity Relationship


  • Enzyme Activators
  • Enzyme Inhibitors