Enzyme Kinetics and Drugs as Enzyme Inhibitors
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Enzymes are prominent targets for drug design because their catalytic activity may be pathogenic and associated to a large variety of diseases. This can be seen from the fact that almost 50% of all drugs are enzyme inhibitors (Hopkin and Groom, 2002). According to a bcc Research analysis the global market for enzyme inhibitors was valued US$ 104.4 billion for 2010 and estimated to reach about US$ 127.4 billion by 2016 (Dewan, 2012). As the number of published enzyme crystal structures steadily increases the search for structure-based drug/inhibitor design via computational screening of huge chemical databases has become possible (Śledź and Caflisch, 2018; Supuran, 2017). In this chapter, the main types of enzyme inhibition have been described and examples for their application in areas such as diabetes, cardiovascular diseases, cancer, or psychiatric disorders are given. Against the background of an improved health care for an ageing population, research activities with the aim to develop new drugs for treatment of complex biological malfunctions will remain of utmost importance in the future including the design of novel multi-target-directed ligands (Ramsay and Tipton, 2017; Jankowska et al., 2018).
MAO Inhibitors: Predicting Response/Maximizing Efficacy
Mark S. Gold, R. Bruce Lydiard, John S. Carman in Advances in Psychopharmacology: Predicting and Improving Treatment Response, 2018
“Endogenous” often has been used loosely to refer to the more seriously impaired, hospitalized patient population. Sometimes it has included criteria of typical vegetative symptoms (anorexia, early morning awakening, diurnal mood variation) or nonreactivity of mood (as would better correlate with the DSM III subtype “melancholia”).22 In general it includes the group of patients who have the highest rate of response to tricyclic antidepressants or ECT. Early studies, in particular that of the respected British Medical Research Council23 and an NIMH collaborative study,24 found MAO inhibitors not to be significantly better than placebo in this population. However, these early studies suffer the compelling criticism that they did not employ a sufficiently high dose of phenelzine (they used a standard dose of 45 mg/day). More current research has demonstrated that a minimum dose of 60 mg/day is necessary to achieve platelet (and by extension, brain) MAO inhibition greater than 80% in a majority of patients.15 This degree of enzyme inhibition is highly correlated with therapeutic response.15 Unfortunately, there is no way to predict effective dosage for a specific individual without using laboratory assays for platelet MAO inhibition. Yet, these findings do suggest that a standard dose of 45 mg/day of phenelzine was inadequate for the majority of patients in this and other early studies.
General pharmacology
Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani in Pharmacology in 7 Days for Medical Students, 2018
In clinical practice, the phenomenon of enzyme inhibition is sometimes exploited for the benefit of the patient. A classical example is that of ethanol-disulfiram interaction. Ethanol (alcohol) is normally metabolised first to acetaldehyde by a hepatic enzyme alcohol dehydrogenase, and then to acetate by aldehyde dehydrogenase. Disulfiram, a drug used as aversion therapy to discourage people from taking alcohol, inhibits aldehyde dehydrogenase leading to a rise in acetaldehyde concentrations. Acetaldehyde produces extremely unpleasant (though not harmful) effects including tachycardia, hyperventilation, flushing and panic. Metronidazole, an antimicrobial agent also inhibits aldehyde dehydrogenase enzyme and thus patients on metronidazole therapy are advised to avoid alcohol for the duration of the therapy.
Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Zofia Chrienova, Eugenie Nepovimova, Rudolf Andrys, Rafael Dolezal, Jana Janockova, Lubica Muckova, Lenka Fabova, Ondrej Soukup, Patrik Oleksak, Martin Valis, Jan Korabecny, José Marco-Contelles, Kamil Kuca
To gain further insight into the mechanism of hAChE inhibition, an enzyme kinetic study was performed on the most potent AChE inhibitor of the series (23). The graphical presentation of the steady-state inhibition data of compound 23 for hAChE is demonstrated in Figure 1. The analysis of the direct plots revealed a reduction of Vmax, whereas Km remained unchanged. These findings are consistent with a non-competitive mode of enzyme inhibition. In case of AChE, it means that the preferential binding site of propargyltacrines is the peripheral anionic site (PAS). From the perspective of AD therapy, this is a highly desirable effect since aggregation of amyloid-beta protein (Aβ) and subsequent neurotoxic cascade are catalysed particularly by the PAS of AChE39. Replots of the slope versus concentration of 23 gave an estimate of the competitive inhibition constant (Ki) of 12.39 ± 1.40 nM, which is consistent with the IC50 (hAChE) value obtained above.
Enzyme-assisted modification of flavonoids from Matricaria chamomilla: antioxidant activity and inhibitory effect on digestive enzymes
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Elida Paula Dini de Franco, Fabiano Jares Contesini, Bianca Lima da Silva, Anna Maria Alves de Piloto Fernandes, Camila Wielewski Leme, João Pedro Gonçalves Cirino, Paula Renata Bueno Campos, Patrícia de Oliveira Carvalho
In a recent study, the ethanolic extract of Chamomilla recutita inhibited lipase activity (86.6 ± 0.3%) in addition to having high antioxidant and anti-glycation capacities33. While EC50 values have shown the potency of the natural compound, more valuable information can be obtained from the kinetics of inhibition by individual compounds or a mixture of compounds from the natural extract. The components of chamomile showed a non-competitive inhibition on glucosidase activity and a mixed inhibition on lipase activity (Figure 2). When an inhibitor binds to the enzyme and/or enzyme–substrate (ES) complex it is defined as non-competitive inhibition, in which the inhibitor affects only Vmax of the reaction, but has no effect on ES complex formation. Mixed inhibition occurs when the inhibitor binds at a distinct site from the active site, but with simultaneous formation of an enzyme–inhibitor (EI) complex in a competitive manner and an enzyme–substrate–inhibitor (ESI) complex in a non-competitive way. Probably this result was due to the mixture of compounds found in the chamomile infusion containing compounds with both types of inhibition, as well as the high efficiency of the bioconversion reaction, which led to the conversion of active compounds to even more active metabolites that can act as enzyme inhibitors. Gholamhoseinian et al.34 found similar results showing that components of Levisticum officinale can bind to the enzyme or ES complex, blocking the pancreatic lipase activity.
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.
Related Knowledge Centers
- Active Site
- Chemical Reaction
- Enzyme
- Enzyme Assay
- Enzyme Catalysis
- Molecule
- Protein
- Substrate
- Product
- Rate-Determining Step