Are improper kinetic models hampering drug development?

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.

Structural Analysis of Simultaneous Activation and Inhibition of γ-Secretase Activity in Development of Drugs for Alzheimer’s disease

“…5). These observations are in agreement with the activity studies which showed that the biphasic-drugs are uncompetitive inhibitors (10,11). The uncompetitive inhibitors are not acceptable in any of the drug-development strategies with γ-secretase as the target.…”

“…We used molecular structures to extend our earlier mechanistic studies of biphasic dose-response in measurements of γ-secretase activity (7,10,11). The presented structural studies are in agreement with conclusions from the earlier activity studies with biphasic-drugs (6,8,(10)(11)(12)15). Multiple drug molecules that bind to γ-secretase can produce the biphasic dose-response by selectively acting on different steps in the catalytic cycle (Figs.…”

“…1). These results indicate concurrent binding at the activation and inhibition sites (10,11,17). The biphasic profiles show Hill´s coefficients that are higher than one ( Fig.…”

“…Multiple studies also indicated that the same drugs can sometimes bind to different sites (37,(42)(43)(44)(45). However, to our knowledge, the functional consequences of multiple enzyme-drug interactions have been explored only in our mechanistic studies of biphasic dose-response (10,11). Fig.…”

“…Activation and inhibition of γ-secretase activity that can be observed in biphasic doseresponse to drugs, are good examples of complex enzymatic mechanism that was not adequately recognized in drug-development studies (2,6,(8)(9)(10)(11)(12)(13)(14). Biphasic dose-response can be observed in cell-cultures (8,10,12,15), in model animals (8,14), and in patient´s plasma in clinical trials (9).…”