China
Africa
Explore chapters and articles related to this topic
Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Not all enzyme inhibitors operate within the active site. Another method is non-competitive inhibition, where drugs can be designed that bind to a non-functional part of the enzyme surface and this physical binding may cause distortion of the protein structure; having the effect of changing the shape of the active site so that the substrate will no longer undergo complementary fit with the enzyme. Hence, the normal biological function is interrupted.
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
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).
Validation and kinetic of enzymatic method for the detection of organophosphate insecticides based on cholinesterase inhibition
Published in Toxicology Mechanisms and Methods, 2020
Inhibitors substances alter the activity of an enzyme by combining with it in a way that influences the binding of substrate thereby preventing it from carrying out its normal function. There are various mechanisms through which enzyme inhibitors can act and effect on the kinetic behavior of enzymes that follow the Michaelis–Menten model depending on the substrate (Sharma 2012). However, when the enzyme is preincubated with the pesticide and the substrate is added afterwards to measure the activity of inhibited enzyme, the inhibition mechanism is found to be noncompetitive. The assay reaction of inhibitor with enzyme represents a noncompetitive inhibition where the inhibitor reacts with the reactive center of the enzyme and then the substrate is added to measure the activity of inhibited enzyme (Rosa et al. 1995; Kok et al. 2002; Rajangam et al. 2018). Noncompetitive inhibitors are not substrate analogs and don’t compete with substrate for the active site of the enzyme. Inhibitors reduce affinity of enzyme to the substrate by binding on sites other than the active site (Sharma 2012). Noncompetitive inhibition of enzyme can be described as follows:
Evaluation of a flavonoids library for inhibition of pancreatic α-amylase towards a structure–activity relationship
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Carina Proença, Marisa Freitas, Daniela Ribeiro, Sara M. Tomé, Eduardo F. T. Oliveira, Matilde F. Viegas, Alberto N. Araújo, Maria J. Ramos, Artur M. S. Silva, Pedro A. Fernandes, Eduarda Fernandes
In accordance, kinetic analysis consisted in the sequential fitting of available models (without inhibition, competitive inhibition, noncompetitive inhibition, uncompetitive inhibition and mixed inhibition), and in the estimation of the kinetic constants (parameters) values. It was possible to observe by the analysis of the sum of the square errors values from the different models, and by the application of F-test and AIC test, that acarbose presents a mixed-type inhibition [see Supporting Information, Figures 1(S)–5(S)], and flavonoids B4 [see Supporting Information, Figures 6(S)–10(S)], C5 (see Supporting Information, Figures 11(S)–15(S)) and D11 [see Supporting Information, Figures 16(S)–20(S)] present a competitive inhibition. Accordingly, Kim et al.55 and Yoon and Robyt,52 also described acarbose as a mixed type inhibitor of α-amylase. To the best of our knowledge, the inhibition type of flavonoids B4, C5 and D11 were studied here for the first time.
Identification of new allosteric sites and modulators of AChE through computational and experimental tools
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Carlos Roca, Carlos Requena, Víctor Sebastián-Pérez, Sony Malhotra, Chris Radoux, Concepción Pérez, Ana Martinez, Juan Antonio Páez, Tom L. Blundell, Nuria E. Campillo
Our main goal in this work was to extend knowledge of the druggable sites of AChE. Since allosterism represents one of the most common and powerful means to regulate protein function, we aimed to study the AChE surface to identify allosteric sites. A combination of the free geometry-based algorithm Fpocket with the Fragment Hotspot maps have allowed the identification of new allosteric binding sites (sites 2 and 3). We carried out a virtual screening study of our in-house library to identify allosteric inhibitors of sites 2 and 3. We validated the predicted hits with experimental studies (in vitro and kinetic studies). These studies have culminated with the identification of allosteric compounds. SC251 has been identified as an allosteric inhibitor of site 2 showing a non-competitive-mixed inhibition. Further MD allowed us to propose a possible action mechanism of this compound. In relation to site 3, VP2.33 and SC035 have been identified. Both compounds show a non-competitive inhibition. Further experimental studies (cooperative activities) have allowed us to validate VP2.33 as an allosteric inhibitor of site 3. These new allosteric modulators are potentially useful pharmacological tools for study of non-hydrolytic functions of cholinergic system.