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Drugs exert their therapeutic effects by interacting with receptors, enzymes, or ion channels that are present throughout the human body. The strength and duration of the interaction between a drug and its target receptor are characterized by the selectivity and specificity of the drug. Selectivity refers to a drug's strong preference for its intended target over other targets. For instance, isoprenaline, a non-selective β-adrenergic agonist, interacts with both β1- and β2-adrenergic receptors...
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Parallel Interrogation of β-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay
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Functional selectivity in GPCR modulator screening.

Terry Kenakin1

  • 1Department of Biological Reagents and Assay Development, GlaxoSmithKline Research, and Development, Research Triangle Park, NC 27709, USA. terry.p.kenakin@gsk.com

Combinatorial Chemistry & High Throughput Screening
|June 10, 2008
PubMed
Summary
This summary is machine-generated.

Optimizing high throughput screening (HTS) for allosteric modulators requires careful consideration of assay conditions. Factors like agonist concentration and probe dependence significantly impact the accurate assessment of modulator potency and efficacy in drug discovery.

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Area of Science:

  • Pharmacology and Drug Discovery
  • Biochemical Assays and Screening

Background:

  • High throughput screening (HTS) typically tests single compound concentrations to identify agonists or antagonists.
  • Assay chemical context in antagonist screening balances sensitivity (low agonist) and window (measurable effect).

Purpose of the Study:

  • To explore critical factors for optimizing HTS of allosteric modulators.
  • To address complexities arising from the saturable nature and probe dependence of allosteric effects.

Main Methods:

  • Conceptual analysis of allosteric modulator behavior within HTS environments.
  • Examination of the interplay between agonist concentration, modulator efficacy, and potency.

Main Results:

  • The saturable nature of allosteric effects can decouple observed response (e.g., % inhibition) from potency.
  • Probe dependence is a significant concern when the physiological agonist is unsuitable for screening (e.g., HIV-1 entry).
  • Assay chemical context critically influences allosteric modulator potency due to complex interactions.

Conclusions:

  • Optimal agonist concentrations in HTS assays may need adjustment to enhance sensitivity to allosteric modulators.
  • Balancing agonist levels is crucial for potentiators to maintain a measurable window for increased agonist effect.
  • Understanding these factors is essential for accurate and reliable HTS of allosteric modulators.