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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The term “enzyme kinetics” is in so far somewhat misleading as one might draw the conclusion from it that the basic principles of chemical kinetics are not valid in this area, which is of course not the case. Reactions catalyzed by bioactive material likewise depend on parameters like concentration, temperature, etc.—the peculiarity is that during the reaction an intermediate is involved which is in equilibrium with the reactants. As it is characteristic for catalysts, enzymes catalyze a reaction in both directions, which is of considerable importance for organic synthesis. Irrespective of that, a treatment of enzyme kinetics is based on the interaction between a macromolecule and a small ligand that normally is the substrate but which can also be an inhibitor, an activator, a co-factor, etc. Because of the usually large differences in particle size between enzymes (10 to 100 nm) and substrate molecules (e.g., ~0.7 nm for glucose), enzyme kinetics marks the transition between homogeneous and heterogeneous catalysis and is therefore sometimes named micro-heterogeneous catalysis. As in case of heterogeneous catalysis, enzyme-catalyzed reactions show the phenomenon of substrate saturation.
Identification Of Receptors In Vitro
Published in William C. Eckelman, Lelio G. Colombetti, Receptor-Binding Radiotracers, 2019
Just as Equation 2 is analogous to a simple situation in enzyme kinetics, Equation 13 for competitive inhibition of binding is analogous to the following situation: E + I ⇋ EI, and E + S ⇋ ES → E + P. That reaction scheme also gives an apparent change in Km, with no change in Vmax. The physical picture is that the substrate and inhibitor bind to the enzyme in a mutually exclusive manner, also analogous to the picture for competitive inhibition of binding. It is worth noting that competitive inhibition, for either enzyme or binding kinetics, does not imply that the substrate and inhibitor bind to the same physical location on the receptor or enzyme — it is enough that their bindings be mutually exclusive.
Design of Nerve-to-Muscle Information Systems
Published in Peter W. Hochachka, Muscles as Molecular and Metabolic Machines, 2019
A second reason why channel fluxes may be less than theoretically expected is because most channels show saturation kinetics. In the Michaelis-Menten model of enzyme kinetics, the velocity of reaction reaches a saturating value (Vmax) at high substrate concentration because substrate molecules compete for binding to active sites, and each enzyme takes a finite time to convert the bound substrate into products and to release them. Similarly, ionic channels can be regarded as catalysts with a limited number of binding sites and taking a finite time to process their substrates.
Mixed and non-competitive enzyme inhibition: underlying mechanisms and mechanistic irrelevance of the formal two-site model
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Prompted to “write a definition of mixed-type enzyme inhibition”, ChatGPT elaborated the following composition: Mixed-type enzyme inhibition is a form of enzyme inhibition where the inhibitor can bind to both the free enzyme and the enzyme-substrate complex, resulting in distinct effects on both the enzyme’s catalytic activity and its affinity for the substrate. In mixed-type inhibition, the inhibitor can interact with the enzyme at either the active or a separate allosteric site. […]Mixed-type enzyme inhibition is a complex regulatory mechanism that can have important implications in various biological processes and the development of therapeutic strategies targeting enzyme activity. Understanding the nature of mixed-type inhibition is crucial for studying enzyme kinetics, drug discovery, and the design of effective enzyme inhibitors. Because the algorithms of ChatGPT have been trained using a massive amount of text data, the response it provided can be considered as a representative description of mixed inhibition that aligns with the general understanding presented in articles, books and other scientific publications.
Power of integrating PBPK with PBBM (PBPK-BM): a single model predicting food effect, gender impact, drug-drug interactions and bioequivalence in fasting & fed conditions
Published in Xenobiotica, 2023
Rajkumar Boddu, Sivacharan Kollipara, Gautam Vijaywargi, Tausif Ahmed
The API metabolised to ortho- and para hydroxylated derivatives and various beta-oxidation products through CYP3A4 as observed from literature reported in vitro studies. In the current integrated PBPK-BM model, while the metabolism kinetics pertaining to CYP3A4 were incorporated, only parent drug was simulated but metabolites were not simulated. This is because bioequivalence as per the USFDA guidance is to be established only for parent drugs but not for metabolites. Moreover, as the objective of the current model also is to simulate food effect, gender impact and DDI’s, it was decided not to include metabolites as it may complicate the model. Hence only single metabolism kinetics pertaining to CYP3A4 has been included in gut as well as in PBPK locations. For metabolite kinetics, the data available from USFDA clinical and biopharmaceutics summary was utilised as follows: Km- 71.8 ± 6.7 µM and Vmax −1.07 ± 0.04 nmol/min/mg microsomal protein (study performed in hepatic microsomes, values corresponding to unbound data). Further these values were converted into the units of mg/s or mg/s/mg-enz for Vmax and mg/L for Km using the unit converter feature available in Gastroplus. Finally, to capture the intestinal metabolism, the Vmax and Km values of CYP3A4 in gut were optimised manually. The final optimised enzyme kinetics were detailed in Table 1.
Modeling principles of protective thyroid blocking
Published in International Journal of Radiation Biology, 2022
Alexis Rump, Stefan Eder, Cornelius Hermann, Andreas Lamkowski, Manabu Kinoshita, Tetsuo Yamamoto, Junya Take, Michael Abend, Nariyoshi Shinomiya, Matthias Port
In the case Michaelis-Menten kinetics are used to describe an exchange process between two compartments, it may be convenient to use molar substance amounts instead of concentrations. This requires to know the volume of distribution of the source compartment (Vs in l). In that case C becomes m (= C*Vs in µmol), Km becomes Km# (= Km*Vs in µmol). T and Tmax are also multiplied by Vs and Tmax# expressed in µmol*d−1. The equation with its original units is probably more familiar to most scientists as Michaelis-Menten kinetics are often associated with enzyme kinetics, but the derived variable units are probably more convenient when running computations using a compartment model with Michaelis-Menten kinetics describing a saturable transport process.