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Radiolabeled Enzyme Inhibitors
Published in William C. Eckelman, Lelio G. Colombetti, 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
Ticarcillin–Clavulanic Acid
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Clavulanic acid acts via inhibition of beta-lactamase enzymes (Bush, 1988; see Chapter 13, Beta-lactamase inhibitors). beta-lactamases are enzymes produced by bacteria that degrade or modify beta-lactam drugs before they reach the penicillin-binding proteins. Clavulanic acid contains a beta-lactam ring that binds the enzyme at its active site. Initially, it acts as a competitive inhibitor, but once bound, there is also acetylation of the enzyme and hydrolysis of the amide bond, leading to irreversible inhibition of the enzyme (Rolin-son, 1991; Livermore, 1993). It acts as a suicide inhibitor. The clavulanic acid, therefore, protects the beta-lactam drug from the beta-lactamase enzyme.
Affinity Modification — Organic Chemistry
Published in Dmitri G. Knorre, Valentin V. Vlassov, Affinity Modification of Biopolymers, 1989
Dmitri G. Knorre, Valentin V. Vlassov
It should be noted that detailed mechanisms of many of the reactions which are considered as suicide inhibition due to the formation of reactive species by the enzymes remain to be investigated. The described mechanisms of formation of reactive species are in many cases hypothetical since experimental studies of the very short-living intermediates and structural analysis of the modified enzymes are related to considerable difficulties. First, detailed chemical and physicochemical studies of enzymes modified with substrate analogues have demonstrated that in some cases where the usual paradigm could suggest suicidal inhibition through the formation of highly reactive intermediate species; in fact, the usual affinity modification takes place. Thus, irreversible inhibitors of chymotrypsin, derivatives of 6- chloro-2-pyrone, can be thought to be converted to highly reactive acyl chlorides upon enzymatic lactone hydrolysis and acyl enzyme formation.
A comprehensive review of cytochrome P450 2E1 for xenobiotic metabolism
Published in Drug Metabolism Reviews, 2019
Jingxuan Chen, Sibo Jiang, Jin Wang, Jwala Renukuntla, Suman Sirimulla, Jianjun Chen
Diallyl sulfide (DAS), a flavor compound derived from garlic, is converted to diallyl sulfoxide and diallyl sulfone by CYP2E1 (Brady et al. 1991). Both DAS and the sulfoxide have been demonstrated to be competitive inhibitors of the enzyme, yet the sulfone is a suicide inhibitor of CYP2E1 (Yang et al. 2001). By selectively inhibiting CYP2E1 in hepatic VL-17A cells (Swaminathan et al. 2013), they are capable of inhibiting not only alcohol- and drug-mediated cellular toxicities but also HIV protein- and diabetes-mediated toxicities (Rao et al. 2015). However, DAS also induces apoptosis at a relatively high concentration (e.g. 100 μM) in human malignant neuroblastoma SH-SY5Y cells (Karmakar et al. 2007). Recently, diallyl ether and allyl methyl sulfide have been demonstrated to have higher efficacy and lower toxicity than DAS (Ki = 3.1, 4.4, and 6.3 μM, respectively; IC50 = 6.3, 11.4, and 17.3 μM, respectively) (Rahman et al. 2017). Other DAS analogs, such as thiophene, 2-prop-2-enoxyacetamide, were also suggested as CYP2E1 inhibitors. These compounds are used as tools for both in vitro and in vivo studies involving CYP2E1 inhibition, especially for examining xenobiotic-induced toxicity and disease pathogenesis mediated by CYP2E1 (Rahman et al. 2018).
Adding double carbapenem therapy to the armamentarium against carbapenem-resistant Enterobacteriaceae bloodstream infections
Published in Infectious Diseases, 2019
Bryan P. White, Smit Patel, Janice Tsui, Daniel B. Chastain
BSIs due to CRE are associated with high in-hospital mortality rates and are a daunting challenge for healthcare professionals to treat due to the lack of optimal treatment or guidelines [23]. Administration of two different carbapenems, aptly known as double carbapenem therapy, has recently emerged as a promising option to treat CRE BSIs. Mechanistically, it has been thought that one of the carbapenems, particularly ertapenem, acts as a suicide inhibitor of KPC enzymes allowing the second carbapenem to have maximum bactericidal activity [22,24]. On the other hand, in a recent computational analysis examining binding complexes with Ambler class A, B, and D carbapenemases, ertapenem was observed to bind in a weak and reversible manner [25]. While the precise mechanism has not been fully elucidated, superior in vitro and in vivo efficacy of ertapenem-containing double carbapenem strategies has been observed against KPC-producing isolates [22]. In the following sections, we review the available in vitro, in vivo, and clinical efficacy data.
Recent advances in computational design of potent aromatase inhibitors: open-eye on endocrine-resistant breast cancers
Published in Expert Opinion on Drug Discovery, 2019
Angelo Spinello, Ida Ritacco, Alessandra Magistrato
Despite its clinical failure, FDZ, able to establish a coordination bond to the iron atom of the heme, boosted the screening of nitrogen-containing heterocycles, leading to the discovery of the third-generation AIs, letrozole and anastrozole (LTZ, ANZ, Figure 1), which were approved for ER+ BC clinical treatment in the late 1990s. Unlike previous AIs, these nonsteroidal inhibitors exhibit a nearly complete selectivity towards HA at clinical doses [54]. Their discovery came along also with that of the suicide inhibitor exemestane (EXE), approved in 1999 [46]. Many years after its approval EXE was trapped in complex with HA by X-ray crystallography [55], providing critical insights on its mechanism of action.