Overview of HIV Infection
Mark J. Rosen, James M. Beck in Human Immunodeficiency Virus and the Lung, 1998
superior to TMP-SMX in efficacy (86-92). Trimethoprim and sulfamethoxazole both act to inhibit key enzymatic steps in folate metabolism. Trimethoprim inhibits dihydrofolate reductase (DHFR), preventing the synthesis of tetrahydrofolate from dihydrofolate, whereas sulfamethoxazole acts on dihydropteroate synthase (DHPS) to prevent the conversion of p-aminobenzoate to dihydrofolic acid. Although trimethoprim alone has no demonstrable antipneumocystic activity, together these compounds produce a synergistic inhibition of P.carinii. Significantly, neither of these two agents is the most avid enzyme inhibitor in their class. Pyrimethamine, trimetrexate, and methotrexate are orders of magnitude more inhibitory for DHFR, whereas many sulfones and sulfonamides show greater inhibition of DHPS. However, TMP-SMX benefits from the availability of a single-combination medication, excellent bioavailability, similar half-lives, and two decades of clinical experience. Moreover, with the rat model, Hughes and colleagues have recently demonstrated the combination of TMP and SMX to be the most potent inhibitor of PCP among commonly used medications when used in combination (93).
General toxicology
Timbrell John in Study Toxicology Through Questions, 2017
treatments. Alternatively either compound may be an enzyme inhibitor. If B was either an enzyme inducer or inhibitor it might alter the metabolism of A in such a way as to increase its toxicity. Thus, a hypothesis which may explain the results is that compound is metabolised by a detoxication pathway which is blocked by compound . Compound is not toxic to either the liver or thymus. The combination of and leads to either an increased level of unchanged which is toxic to the thymus and causes increased liver weight or alters the metabolism of A so as to increase production of a toxic metabolite. The increased liver weight could be due to the enzyme induction caused by the parent compound or a metabolite which may be the metabolite responsible for the thymus toxicity. Similar effects are observed with TCDD (dioxin).
Radiolabeled Enzyme Inhibitors
William C. Eckelman, Lelio G. Colombetti in Receptor-Binding Radiotracers, 2019
The requirements for a successful suicide inhibitor are It must be a substrate for the target enzyme. The closer the inhibitor resembles the natural substrate, the more likely the inhibitor will workIt must be converted from a chemically inactive compound to a chemically reactive compound by the target enzymeThe reactive group must be generated within bonding distance of a nucleophilic residue in the enzyme’s active siteThe rate of covalent attachment of the inhibitor to the active site must be faster than the rate of dissociation of the enzyme-inhibitor complex
Models of enzyme inhibition and apparent dissociation constants from kinetic analysis to study the differential inhibition of aldose reductase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Francesco Balestri, Mario Cappiello, Roberta Moschini, Umberto Mura, Antonella Del-Corso
A variety of graphical approaches have been proposed to disclose and characterise incomplete inhibition16–24. In this study, the rate equations derived from the classical approach16,17, considering the inhibitor targeting the free enzyme or the enzyme-substrate complex were used to fit experimental rate measurements through non-linear regression analysis. In this regard, the trend of the appKM/appkcat versus the inhibitor concentration is proposed as a useful tool to easily disclose the occurrence of an incomplete inhibition. Moreover, the analysis of both complete and incomplete inhibition was here performed also through a non-classical approach, in which it is the substrate that interacts with either the free enzyme or the enzyme-inhibitor complex.
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.
Synthesis, in vitro enzyme activity and molecular docking studies of new benzylamine-sulfonamide derivatives as selective MAO-B inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Begüm Nurpelin Sağlık, Derya Osmaniye, Ulviye Acar Çevik, Serkan Levent, Betül Kaya Çavuşoğlu, Özlem Atlı Eklioğlu, Yusuf Özkay, Ali Savaş Koparal, Zafer Asım Kaplancıklı
Irreversible enzymatic inhibition involves covalent interactions between the substrate and the enzyme. In contrast, there are non-covalent interactions such as hydrophobic interactions, ionic bonds, and hydrogen bonds involved in reversible inhibition. In this type of inhibition, inhibitors bind to the enzymes without forming any chemical bonds; thus, the enzyme-inhibitor complex could be separated quickly because non-covalent interactions can form rapidly and break easily. Furthermore, reversible inhibitors have a lower risk of side effects than irreversible inhibitors owing to their non-covalent binding ability. Consequently, compounds 4i and 4t, whose inhibition types were determined to be reversible and non-competitive, have pharmaceutical importance in contrast to irreversible hydrazine-type MAO inhibitors.
Related Knowledge Centers
- Active Site
- Chemical Reaction
- Enzyme
- Enzyme Assay
- Enzyme Catalysis
- Molecule
- Protein
- Substrate
- Product
- Rate-Determining Step