Are improper kinetic models hampering drug development?
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.
Department of Chemistry, Carleton University , Ottawa, ON , Canada.
Ryan
R
Walsh
Alzheimer’s disease; Amyloid; Disease; Drug development; Empirical models; Enzyme inhibition; Enzyme kinetics; Gamma-secretase; Irreproducibility; Reproducibility