Dissertation
Kinetics Beyond the Steady State: Numerical Modeling of Time-Dependent Inhibition
Doctor of Philosophy (PhD), Washington State University
01/2020
Handle:
https://hdl.handle.net/2376/117700
Abstract
Time-dependent inhibition (TDI) of drug-metabolizing enzymes is a known obstacle to nascent drug candidates in a drug discovery pipeline that is lengthy and expensive. The work herein is focused on modernizing the analysis methodology of TDI so that kinetics scientists can avoid unnecessary exclusion of drugs from the development process. In the first study, spectroscopic experiments were used to examine some mechanistic details of the inactivation of cytochrome P450 2D6 by methylenedioxymethamphetamine (MDMA). In contrast to past results in the literature, our work supported a reversible binding inhibition mode for MDMA and further concluded that heterogeneity existed concerning the participation of the protein population in MDMA metabolism. In the second study, we applied the results of the first study by employing a numerical modeling technique to TDI kinetics experiments that would normally be undertaken in the drug discovery pipeline. Numerical models representative of reversible and irreversible binding were tested on the kinetics data and supported the conclusions of the first publication. In addition, this publication included the first reports of numerical model projections. Here, the best-fit numerical model was made to predict the results of inactivation over a large time range and determined that the reversibility of inactivation was significantly faster than estimates of the regeneration rate of the protein in vivo, negating the consequences of TDI. In the third study, our numerical modeling technique was expanded to include two inhibitors of aldehyde oxidase (AO). Reversible inhibition was again indicated in these TDI experiments. A second kinetic analysis was performed in this study wherein data measuring rates of metabolite formation over time were modeled. The improvements of numerical modeling over classical, steady-state techniques were discussed as well as the impact of a high precision kinetics prediction tool.
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Details
- Title
- Kinetics Beyond the Steady State: Numerical Modeling of Time-Dependent Inhibition
- Creators
- John Thomas Rodgers
- Contributors
- Jeffrey P. Jones (Advisor)Chulhee Kang (Committee Member)Cliff Berkman (Committee Member)Mary Paine (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Chemistry, Department of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 157
- Identifiers
- 99900581704201842
- Language
- English
- Resource Type
- Dissertation