CHAPTER 2: Identifying and Quantifying Allosteric Drug Function

Research output: ResearchChapter

Abstract

Allosteric molecules are fundamentally different from molecules that bind to the natural receptor binding pockets for endogenous hormones and neurotransmitters and this gives them a unique repertoire of dose-response behaviors. The underlying principle that differentiates allosteric from orthosteric molecules is the concept of permissiveness. Specifically, allosteric ligands may permit some aspects of the receptor system to function; in contrast, orthosteric ligands do not. Orthosteric ligands are pre-emptive in that if an orthosteric ligand is bound to the natural receptor binding site, then no other molecule can bind to the receptor, i.e. steric hindrance prevents further interaction. This being the case, the ligand-bound species are somewhat uniform, with respect to different orthosteric ligands, in that the observed properties are related only to the bound new molecule and not to the endogenous natural ligand. For instance, a β-blocker such as propranolol pre-empts the binding of natural catchecholamines in the same way as does the orthosteric β-blocker pindolol; the differences in this regard only relate to potency. The important difference between orthosteric and allosteric systems is that, in orthosteric systems there never is a pharmacologically relevant receptor species with both the orthosteric ligand and natural ligand bound simultaneously. In contrast, the pharmacologically relevant receptor species in allosteric systems has both the allosteric and the natural ligand bound simultaneously. This permissive nature makes allosteric receptor systems extremely flexible with respect to the fine tuning of receptor function. Within the repertoire of allosteric receptor behaviors lie a number of behaviors that can appear to be identical to the behaviors seen with orthosteric molecules. Failure to recognize which of these modes of action are operative with respect to drug action can lead to dissimulations in the interpretation of drug behavior. Therefore, it is important to determine whether a ligand interaction is orthosteric or allosteric in nature. Clearly if potentiation of effect is observed, this can only occur allosterically. However, allosteric antagonism can appear identical to simple competitive antagonism if it is surmountable (no depression of maximal response), and orthosteric non-competitive antagonism if it is insurmountable (depressed maximal response).

LanguageEnglish (US)
Title of host publicationAllosterism in Drug Discovery
PublisherRoyal Society of Chemistry
Pages24-39
Number of pages16
Volume2017-January
Edition56
DOIs
StatePublished - 2017

Publication series

NameRSC Drug Discovery Series
No.56
Volume2017-January
ISSN (Print)20413203
ISSN (Electronic)20413211

Fingerprint

Ligands
Pharmaceutical Preparations
Permissiveness
Pindolol
Propranolol
Neurotransmitter Agents
Binding Sites
Hormones

ASJC Scopus subject areas

  • Drug Discovery

Cite this

Kenakin, T. (2017). CHAPTER 2: Identifying and Quantifying Allosteric Drug Function. In Allosterism in Drug Discovery (56 ed., Vol. 2017-January, pp. 24-39). (RSC Drug Discovery Series; Vol. 2017-January, No. 56). Royal Society of Chemistry. DOI: 10.1039/9781782629276-00024

CHAPTER 2 : Identifying and Quantifying Allosteric Drug Function. / Kenakin, Terry.

Allosterism in Drug Discovery. Vol. 2017-January 56. ed. Royal Society of Chemistry, 2017. p. 24-39 (RSC Drug Discovery Series; Vol. 2017-January, No. 56).

Research output: ResearchChapter

Kenakin, T 2017, CHAPTER 2: Identifying and Quantifying Allosteric Drug Function. in Allosterism in Drug Discovery. 56 edn, vol. 2017-January, RSC Drug Discovery Series, no. 56, vol. 2017-January, Royal Society of Chemistry, pp. 24-39. DOI: 10.1039/9781782629276-00024
Kenakin T. CHAPTER 2: Identifying and Quantifying Allosteric Drug Function. In Allosterism in Drug Discovery. 56 ed. Vol. 2017-January. Royal Society of Chemistry. 2017. p. 24-39. (RSC Drug Discovery Series; 56). Available from, DOI: 10.1039/9781782629276-00024
Kenakin, Terry. / CHAPTER 2 : Identifying and Quantifying Allosteric Drug Function. Allosterism in Drug Discovery. Vol. 2017-January 56. ed. Royal Society of Chemistry, 2017. pp. 24-39 (RSC Drug Discovery Series; 56).
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