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000892139 1001_ $$00000-0001-5222-1137$$aJaladanki, Chaitanya K.$$b0
000892139 245__ $$aReactive Metabolites from Thiazole-Containing Drugs: Quantum Chemical Insights into Biotransformation and Toxicity
000892139 260__ $$aNew York, NY$$bACS Publ.$$c2021
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000892139 520__ $$aDrugs containing thiazole and aminothiazole groups are known to generate reactive metabolites (RMs) catalyzed by cytochrome P450s (CYPs). These RMs can covalently modify essential cellular macromolecules and lead to toxicity and induce idiosyncratic adverse drug reactions. Molecular docking and quantum chemical hybrid DFT study were carried out to explore the molecular mechanisms involved in the biotransformation of thiazole (TZ) and aminothiazole (ATZ) groups leading to RM epoxide, S-oxide, N-oxide, and oxaziridine. The energy barrier required for the epoxidation is 13.63 kcal/mol, that is lower than that of S-oxidation, N-oxidation, and oxaziridine formation (14.56, 17.90, and 20.20, kcal/mol respectively). The presence of the amino group in ATZ further facilitates all the metabolic pathways, for example, the barrier for the epoxidation reaction is reduced by ∼2.5 kcal/mol. Some of the RMs/their isomers are highly electrophilic and tend to form covalent bonds with nucleophilic amino acids, finally leading to the formation of metabolic intermediate complexes (MICs). The energy profiles of these competitive pathways have also been explored
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000892139 7001_ $$0P:(DE-HGF)0$$aKhatun, Samima$$b1
000892139 7001_ $$0P:(DE-Juel1)172663$$aGohlke, Holger$$b2
000892139 7001_ $$00000-0002-7064-8561$$aBharatam, Prasad V.$$b3$$eCorresponding author
000892139 773__ $$0PERI:(DE-600)2003547-0$$a10.1021/acs.chemrestox.0c00450$$gp. acs.chemrestox.0c00450$$n6$$p1503–1517$$tChemical research in toxicology$$v34$$x1520-5010$$y2021
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000892139 8564_ $$uhttps://juser.fz-juelich.de/record/892139/files/tx-2020-00450wR1-manuscript_w_accepted_changes.pdf$$yPublished on 2021-04-26. Available in OpenAccess from 2022-04-26.
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