Walsh2014 - Inhibition kinetics of DAPT on APP Cleavage

Walsh2014 - Inhibition kinetics of DAPT on
APP Cleavage

This model is described in the article:

Are improper kinetic models
hampering drug development?

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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