Walsh2014 - Inhibition kinetics of DAPT on APP Cleavage

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Walsh2014 - Inhibition kinetics of DAPT on APP Cleavage

This model is described in the article:

Walsh R.
PeerJ 2014; 2: e649

Abstract:

Reproducibility of biological data is a significant problem in research today. One potential contributor to this, which has received little attention, is the over complication of enzyme kinetic inhibition models. The over complication of inhibitory models stems from the common use of the inhibitory term (1 + [I]/Ki ), an equilibrium binding term that does not distinguish between inhibitor binding and inhibitory effect. Since its initial appearance in the literature, around a century ago, the perceived mechanistic methods used in its production have spurred countless inhibitory equations. These equations are overly complex and are seldom compared to each other, which has destroyed their usefulness resulting in the proliferation and regulatory acceptance of simpler models such as IC50s for drug characterization. However, empirical analysis of inhibitory data recognizing the clear distinctions between inhibitor binding and inhibitory effect can produce simple logical inhibition models. In contrast to the common divergent practice of generating new inhibitory models for every inhibitory situation that presents itself. The empirical approach to inhibition modeling presented here is broadly applicable allowing easy comparison and rational analysis of drug interactions. To demonstrate this, a simple kinetic model of DAPT, a compound that both activates and inhibits ?-secretase is examined using excel. The empirical kinetic method described here provides an improved way of probing disease mechanisms, expanding the investigation of possible therapeutic interventions.

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Format
SBML (L3V1)
Related Publication
  • Are improper kinetic models hampering drug development?
  • Walsh R
  • PeerJ , 0/ 2014 , Volume 2 , pages: e649
  • Department of Chemistry, Carleton University , Ottawa, ON , Canada.
  • Reproducibility of biological data is a significant problem in research today. One potential contributor to this, which has received little attention, is the over complication of enzyme kinetic inhibition models. The over complication of inhibitory models stems from the common use of the inhibitory term (1 + [I]/Ki ), an equilibrium binding term that does not distinguish between inhibitor binding and inhibitory effect. Since its initial appearance in the literature, around a century ago, the perceived mechanistic methods used in its production have spurred countless inhibitory equations. These equations are overly complex and are seldom compared to each other, which has destroyed their usefulness resulting in the proliferation and regulatory acceptance of simpler models such as IC50s for drug characterization. However, empirical analysis of inhibitory data recognizing the clear distinctions between inhibitor binding and inhibitory effect can produce simple logical inhibition models. In contrast to the common divergent practice of generating new inhibitory models for every inhibitory situation that presents itself. The empirical approach to inhibition modeling presented here is broadly applicable allowing easy comparison and rational analysis of drug interactions. To demonstrate this, a simple kinetic model of DAPT, a compound that both activates and inhibits γ-secretase is examined using excel. The empirical kinetic method described here provides an improved way of probing disease mechanisms, expanding the investigation of possible therapeutic interventions.
Contributors
Thawfeek Varusai

Metadata information

hasTaxon
Taxonomy Homo sapiens
isDescribedBy
hasProperty
Human Disease Ontology Alzheimer's disease
Curation status
Curated
Name Description Size Actions

Model files

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  • Model originally submitted by : Thawfeek Varusai
  • Submitted: Sep 12, 2016 4:03:32 PM
  • Last Modified: Oct 10, 2016 4:39:28 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Oct 10, 2016 4:39:28 PM
    • Submitted by: Thawfeek Varusai
    • With comment: Current version of Walsh2014 - Inhibition kinetics of DAPT on APP Cleavage
  • Version: 1 public model Download this version
    • Submitted on: Sep 12, 2016 4:03:32 PM
    • Submitted by: Thawfeek Varusai
    • With comment: Original import of Walsh2014 - Inhibition kinetics of DAPT on APP Cleavage
Curator's comment:
(added: 12 Sep 2016, 17:48:46, updated: 12 Sep 2016, 17:48:46)
The model was encoded and simulated using Copasi 4.15. Wolfram Mathematica 8 and MS PowerPoint were used to process the figures. The left graph of figure 2C from the paper was simulated. The different curves represent the profile of rate v for different values of the substrate S. S = {15,25,61,92,115,250}