Are improper kinetic models hampering drug development?
- Published
- Accepted
- Subject Areas
- Biochemistry, Mathematical Biology, Neuroscience, Drugs and Devices, Pharmacology
- Keywords
- Enzyme Kinetics, disease, Alzheimer's disease, drug development, gama-secretase, empirical models, amyloid, enzyme inhibition, irreproducibility, Reproducibility
- Copyright
- © 2014 Walsh
- Licence
- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ PrePrints) and either DOI or URL of the article must be cited.
- Cite this article
- 2014. Are improper kinetic models hampering drug development? PeerJ PrePrints 2:e521v1 https://doi.org/10.7287/peerj.preprints.521v1
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. This 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 which both activates and inhibits γ-secretase is examined using excel. The empirical kinetic method described here allows for a more in depth understanding of drug interactions and disease mechanism.
Author Comment
This manuscript is under review at PeerJ.