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The Neuromuscular Junction
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
A noncompetitive antagonist blocks the action of a neurotransmitter, or agonist, by binding to a site on the receptor other than the binding site of the neurotransmitter, or agonist, that is, it is not competing for the same binding site. The site to which the noncompetitive antagonist binds is referred to as an allosteric site, which in general is a site other than the active site of an enzyme that allows the binding of a substance that regulates the enzyme’s activity. An uncompetitive antagonist differs from a noncompetitive neurotransmitter in that it requires receptor activation by the neurotransmitter, or agonist, before it can bind to a separate allosteric binding site. Noncompetitive and uncompetitive antagonists could also be reversible or irreversible.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Allosteric regulation (or control) means the influence of an effector molecule on an enzyme and plays a role in cell signaling (long-range allosteric effects); it binds at a site other than the enzyme’s active site, the allosteric site. This is often accompanied by conformational changes involving protein dynamics. Effector molecules either cause positive allosteric modulation (allosteric activation) or negative allosteric modulation (allosteric inhibition) and are in a broader sense of importance for conformational perturbations on cellular functions and disease states; in other words the allosteric change in one protein may affect the behavior of other proteins downstream. Non-competitive inhibition always means allosteric inhibition but not all allosteric inhibitors act non-competitive. For models explaining the allosteric effect see Monod et al. (1965; concerted model) and Koshland et al. (1966, sequential model).
Computational Neuroscience and Compartmental Modeling
Published in Bahman Zohuri, Patrick J. McDaniel, Electrical Brain Stimulation for the Treatment of Neurological Disorders, 2019
Bahman Zohuri, Patrick J. McDaniel
Figure 3.12 is a stylized depiction of an activated NMDAR. Glutamate is in the glutamate-binding site, and glycine is in the glycine-binding site. The allosteric site, which modulates receptor function when bound to a ligand, is not occupied. NMDARs require the binding of two molecules of glutamate or aspartate and two of glycine.
4-Arylthiosemicarbazide derivatives as a new class of tyrosinase inhibitors and anti-Toxoplasma gondii agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Adrian Bekier, Lidia Węglińska, Agata Paneth, Piotr Paneth, Katarzyna Dzitko
Two scenarios of the molecular mechanism of Tyr inhibition can be proposed from our kinetic studies. Since mixed type of inhibition has been determined quite frequently for this enzyme51, it is apparent that the inhibitor can compete with the substrate for binding space within the enzyme active site, i.e. a pocket around the iron atom, ligated by six histidines. However, two possible structural options can be considered for the other component of the inhibition, originating from the E·S·I ternary complex. The first involves the simultaneous binding of the reactant and inhibitor to the active site of the enzyme. The second consists of the inhibitor binding to an allosteric site. Detailed docking simulations excluded the first possibility on the basis of failure of binding the substrate to the enzyme-inhibitor and of biding inhibitor to enzyme-substrate complexes within the active site. This result is not surprising since the active site is quite tight and buried. Thus, only the second option remains, which is allosteric inhibition at a remote site with unknown mechanism of action or near the active site most likely with steric hindrance preventing substrate from entering/exiting while the inhibitor is bound to the protein.
Cinnamic acid derivatives: inhibitory activity against Escherichia coli β-glucuronidase and structure–activity relationships
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Xing-Nuo Li, Lu-Xia Hua, Tao-Shun Zhou, Ke-Bo Wang, Yuan-Yuan Wu, Mahmoud Emam, Xiao-Ze Bao, Jun Chen, Bin Wei
The inhibition action of six CADs against EcGUS was investigated. In Lineweaver-Burk plots, the location of the intercept of regression lines in the second quadrant for acteoside, martynoside, isoacteoside, acetylacteoside, and isoforsythiaside demonstrated that these compounds were mixed-type inhibitors of EcGUS, with Ki values ranging from 2.8 to 8.3 µM (Figure 3(A–E) and Table 1). This result indicates that these molecules bind to the enzyme at both the allosteric site and active site. In addition, the location of the intercept at the y-axis for CAEE demonstrated that this compound was a relatively strong competitive inhibitor, with a Ki value of 2.7 µM, and CAEE and pNPG competed for the same binding site of EcGUS (Figure 3(F) and Table 1).
The chemical diversity and structure-based discovery of allosteric modulators for the PIF-pocket of protein kinase PDK1
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Xinyuan Xu, Yingyi Chen, Qiang Fu, Duan Ni, Jian Zhang, Xiaolong Li, Shaoyong Lu
A possible strategy to develop non-ATP-competitive inhibitors is the design of selective allosteric modulators of PDK1 through binding to their allosteric sites, which are spatially and topographically distinct from its orthosteric, ATP binding site39,40. Allostery is a very efficient mechanism which regulates the function of biological macromolecules through the binding of an effector to an allosteric site distinct from the orthosteric, active site41–47. Compared to orthosteric ligands that bind to highly conserved orthosteric site, allosteric modulators, by targeting less conserved allosteric sites, offer several remarkable advantages such as greater selectivity, fewer side effects, and lower toxicity46,48–50. Therefore, allostery has been a crucial strategy for the development of non-ATP-competitive kinase inhibitors51,52.