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Pharmacologic Principles
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
The environmental factors influencing the rate of AED biotransformation include environmental chemicals such as pesticides, cigarette smoke and other air pollutants, medicinal drugs, and some foodstuffs such as alcohol via induction or inhibition of drug metabolism. Among AEDs the barbiturates, PHT, and CBZ are inducers of cytochrome P-450 and tend to accelerate biotransformation of other drugs, while VPA, ESM, and MSM tend to have an inhibitory action. In some situations a dual effect occurs: thus PB induces enzymes executing PHT hydroxylation but also uses these same enzymes for its own metabolism, which results in competitive inhibition. Dual action is seen also with alcohol: chronic use induces while acute consumption of alcohol inhibits. An example of noncompetitive inhibition is inhibition of PHT metabolism by isoniazid (reduced Vmax with little change of Km). Differentiation between competitive and noncompetitive inhibition is relevant in the clinical consequences: noncompetitive inhibitor causes a continuous rise during its presence, while a competitive inhibitor raises the level to a higher plateau where the primary drug is again competing effectively (27,28).
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Competitive inhibitors are of widespread clinical use as therapeutics. In case of competitive inhibition, the active site of the enzyme binds either the substrate (ES) or the inhibitor (EI) but not both inhibitor and substrate (ESI). Competitive inhibitors show structural similarities with the natural substrate and are recognized by the active site. Competitive inhibition can be reversed by increasing the substrate concentration. Product inhibition can be looked at as a special kind of competitive inhibition; for example, hexokinase binds its substrate glucose as well as the product glucose-6-phosphate so that an accumulation of this metabolite is avoided. The rate equation for competitive inhibition is
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.
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
This means that the type of inhibition cannot be taken as a sufficient proof of any given molecular mechanism. For example, although it is true that competitive inhibition is generally caused by inhibitors that, in agreement with the conventional mechanism (Figure 1(A)) bind the active site in competition with the substrate, exceptions where competition results from the binding of allosteric sites have also been reported2,3. In contrast, only on rare occasions do uncompetitive inhibitors actually bind the ES complex4,5. The most common sources of uncompetitive inhibition being, by far, reactions with more than one substrate with compulsory-order mechanisms6,7 where the inhibitor binds to the binding site of the constant substrate.
Mechanism of biotin carboxylase inhibition by ethyl 4-[[2-chloro-5-(phenylcarbamoyl)phenyl]sulphonylamino]benzoate
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Matthew K. Craft, Grover L. Waldrop
Competitive inhibition means that binding of the inhibitor and the substrate to the enzyme are mutually exclusive. This usually indicates that the inhibitor and substrate bind in the same location. The simple explanation for the competitive inhibition patterns observed for SABA1 suggest the inhibitor can bind in either the ATP or biotin binding sites, or both sites simultaneously. To determine if SABA1 can bind in the ATP binding site, biotin binding site or both, multiple inhibition analysis was performed as described by Yonetani and Theorell42. Multiple inhibition analysis is used to define the topological relationship between two different enzyme inhibitors42. Initial velocities are measured while one inhibitor is varied against fixed increasing concentrations of the second inhibitor. The substrates are held constant at subsaturating levels.
The behavior of some chalcones on acetylcholinesterase and carbonic anhydrase activity
Published in Drug and Chemical Toxicology, 2019
Hatice Esra Aslan, Yeliz Demir, Muhammet Serhat Özaslan, Fikret Türkan, Şükrü Beydemir, Ömer Irfan Küfrevioğlu
For hCA I, the IC50 values were found to be 2.08 μM, 4.56 μM, 9.49 μM, 2.74 μM, 1.70 μM, 2.03 μM, and 1.91 μΜ for 2′-hydroxy-4-methoxychalcone, 4-fluorochalcone, 4-methoxychalcone, 4′-hydroxychalcone, 4-nitrochalcone, 4-fluoro-4′-methoxychalcone, and 4,4′-diflurochalcone respectively. The Ki constants were obtained from the Lineweaver–Burk graphs (1/V − 1/[S]), and an inhibition type was found for each chalcones. The Ki constants were found to be 1.83 ± 0.74 μM, 1.92 ± 0.55 μM, 2.42 ± 0.67 μM, 3.52 ± 0.92 μM, 4.15 ± 0.61 μM, 4.57 ± 0.057 μM, and 7.05 ± 2.92 μΜ for 4-fluoro-4′-methoxychalcone, 4,4′-diflurochalcone, 4′-hydroxychalcone, 4-nitrochalcone, 2′-hydroxy-4-methoxychalcone, 4-methoxychalcone and 4-fluorochalcone, respectively (Table 2). All compounds were exhibited competitive inhibition.