Finding a Target
Nathan Keighley in Miraculous Medicines and the Chemistry of Drug Design, 2020
Drugs that target enzymes are designed to inhibit their normal operation. This can be achieved in different ways. Competitive inhibitors mimic the molecular structure of normal substrate so that the drug can bind with a complimentary fit to the active site of the enzyme. This has the effect of blocking the active site, preventing entry of the normal substrate. The necessary reaction with the normal substrate cannot proceed, hence the biological process is subdued. The extent of this effect depends on the concentration of the drug, which in turn determines how many active sites are inhibited out of the plethora of catalytically available enzymes. Also important is the strength of binding of the drug to the active site, which effects the length of time that the drug remains in the active site; impacting the probability of normal biological catalysis happening. The nature of non-covalent interactions; being changeably broken and re-formed results in inhibition occurring dynamically. The weaker the intermolecular forces between the drug and the active site, the greater the proportion of unencumbered enzymes at any one time and the biological process will be inhibited to a lesser extent. The drug must be designed to optimise non-covalent interactions in order to be effective. Alternatively, the drug molecule could perhaps be designed to undergo reaction once in the active site to form a covalent bond to an amino acid residue. This is an irreversible form of inhibition and renders that enzyme molecule redundant.
Biochemical Effects in Animals
Stephen P. Coburn in The Chemistry and Metabolism of 4′-Deoxypyridoxine, 2018
Pyridoxal kinase (E.C. 2.7.1.35) has a broad specificity and may be referred by various names depending on the substrate used in a particular experiment. For consistency, we will use the term, pyridoxal kinase, throughout this discussion even though the original authors may have used an alternate name (e.g., pyridoxine kinase). Also, in the following review of the interaction between deoxypyridoxines and pyridoxal kinases, the reader should keep in mind the problems discussed in the preface in distinguishing between a substrate and a competitive inhibitor. The term competitive inhibitor is used below as used in the original articles and does not necessarily mean that the inhibitor was not a substrate for the enzyme. It is very likely that 4′-deoxypyridoxine was a substrate in every case.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Peter Grunwald in 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
A comprehensive review on tyrosinase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Samaneh Zolghadri, Asieh Bahrami, Mahmud Tareq Hassan Khan, J. Munoz-Munoz, F. Garcia-Molina, F. Garcia-Canovas, Ali Akbar Saboury
The chemical structure of the different substrates is diverse, but the process always requires a step of oxidation/reduction: o-diphenols102,104, ascorbic acid103, aminophenols and o-diamines105, hydroxyhydroquinone109, tetrahydrobiopterines110, tetrahydrofolic acid111 and NADH112.Generally, the mode of inhibition by “true inhibitors” is one of these four types: competitive, uncompetitive, mixed type (competitive/uncompetitive), and noncompetitive. A competitive inhibitor can bind to a free enzyme and prevents substrate binding to the enzyme active site. Regarding the property that tyrosinase is a metalloenzyme, copper chelators such as many aromatic acids, phenolic and poly-phenolic compounds, a few non-aromatic compounds, can inhibit tyrosinase competitively by mimicking the substrate of tyrosinase52,60. Recently, it was found that d-tyrosine negatively regulates melanin synthesis by inhibiting tyrosinase activity, competitively113. In addition, l-tyrosine has been shown as an inhibitor114.
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.
An evaluation of masitinib for treating systemic mastocytosis
Published in Expert Opinion on Pharmacotherapy, 2019
Mariarita Laforgia, Ilaria Marech, Patrizia Nardulli, Concetta Calabrò, Cosimo Damiano Gadaleta, Girolamo Ranieri
In experiment a), researchers have demonstrated that masitinib has two dose-dependent mechanisms of inhibition towards the intracellular domain (amino acids 567–976), normally activated by ATP (with a Km = 9.0 ± 2.0 μM), by using as a substrate of phosphorylation a poly(Glu, Tyr 4:1), which imitates the tyrosine kinase area. At concentration ≤500 nM, masitinib acts as a competitive inhibitor against ATP, while at higher concentrations >1 mM it has a mixed competitive/noncompetitive mechanism of phosphorylation inhibition. Imatinib, on the contrary, is a strictly competitive inhibitor versus ATP at any concentration. A competitive inhibitor links the active site of the protein in a reversible way and is structurally similar to the natural substrate (ATP in the specific case), while a non-competitive inhibitor links the protein in an area of its quaternary structure different from the active site. A mixed inhibitor, on the contrary, binds both the free protein and the substrate/protein complex. Lineweaver–Burk plots present differently on the basis of these mechanisms, with all lines of increasing tested drug concentrations intersecting on the Y-axis for a competitive process, or to the left of the Y-axis for the mixed competitive/noncompetitive one (in pure noncompetitive inhibition lines never intersect Y-axis). Moreover, masitinib showed a half inhibitory concentration IC50 = 200 ± 40 nM towards wild-type c-kit versus the corresponding imatinib’s IC50 = 470 ± 120 nM, more than two-fold quantity.
Related Knowledge Centers
- Antimetabolite
- Biochemistry
- Chemistry
- Enzyme Catalysis
- Enzyme Inhibitor
- Poisoning
- Receptor Antagonist
- Metabolism
- Molecular Binding
- Michaelis–Menten Kinetics