Investigating receptor enzyme activity using time-scale analysis

Tao You, Hong Yue

Research output: Contribution to journalArticle

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Abstract

At early drug discovery, purified protein-based assays are often used to characterise compound potency. In the context of dose response, it is often perceived that a time-independent inhibitor is reversible and a time-dependent inhibitor is irreversible. The legitimacy of this argument is investigated using a simple kinetics model, where it is revealed by model-based analytical analysis and numerical studies that dose response of an irreversible inhibitor may appear time-independent under certain parametric conditions. Hence, the observation of time-independence cannot be used as sole evidence for identification of inhibitor reversibility. It has also been discussed how the synthesis and degradation of a target receptor affect drug inhibition in an in vitro cell-based assay setting. These processes may also influence dose response of an irreversible inhibitor in such a way that it appears time-independent under certain conditions. Furthermore, model-based steady-state analysis reveals the complexity nature of the drug-receptor process.
Original languageEnglish
Pages (from-to)268-276
Number of pages9
JournalIET Systems Biology
Volume9
Issue number6
DOIs
Publication statusPublished - 19 Nov 2015

Fingerprint

Enzyme activity
Receptor
Inhibitor
Enzymes
Time Scales
Dose-response
Assays
Drug Receptors
Drugs
Model-based
Illegitimacy
Steady-state Analysis
Drug Discovery
Reversibility
Proteins
Degradation
Kinetic Model
Systems Analysis
Kinetics
Numerical Study

Keywords

  • biochemistry
  • cellular biophysics
  • drugs
  • enzymes
  • molecular biophysics
  • reaction kinetics

Cite this

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abstract = "At early drug discovery, purified protein-based assays are often used to characterise compound potency. In the context of dose response, it is often perceived that a time-independent inhibitor is reversible and a time-dependent inhibitor is irreversible. The legitimacy of this argument is investigated using a simple kinetics model, where it is revealed by model-based analytical analysis and numerical studies that dose response of an irreversible inhibitor may appear time-independent under certain parametric conditions. Hence, the observation of time-independence cannot be used as sole evidence for identification of inhibitor reversibility. It has also been discussed how the synthesis and degradation of a target receptor affect drug inhibition in an in vitro cell-based assay setting. These processes may also influence dose response of an irreversible inhibitor in such a way that it appears time-independent under certain conditions. Furthermore, model-based steady-state analysis reveals the complexity nature of the drug-receptor process.",
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Investigating receptor enzyme activity using time-scale analysis. / You, Tao; Yue, Hong.

In: IET Systems Biology, Vol. 9, No. 6, 19.11.2015, p. 268-276.

Research output: Contribution to journalArticle

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AU - You, Tao

AU - Yue, Hong

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AB - At early drug discovery, purified protein-based assays are often used to characterise compound potency. In the context of dose response, it is often perceived that a time-independent inhibitor is reversible and a time-dependent inhibitor is irreversible. The legitimacy of this argument is investigated using a simple kinetics model, where it is revealed by model-based analytical analysis and numerical studies that dose response of an irreversible inhibitor may appear time-independent under certain parametric conditions. Hence, the observation of time-independence cannot be used as sole evidence for identification of inhibitor reversibility. It has also been discussed how the synthesis and degradation of a target receptor affect drug inhibition in an in vitro cell-based assay setting. These processes may also influence dose response of an irreversible inhibitor in such a way that it appears time-independent under certain conditions. Furthermore, model-based steady-state analysis reveals the complexity nature of the drug-receptor process.

KW - biochemistry

KW - cellular biophysics

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KW - molecular biophysics

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