Biotransformation of Isoniazid by Cytochromes P450: Analyzing the Molecular Mechanism using Density Functional Theory
| Autor: | Akbar Shaikh, Chaitanya K. Jaladanki, Prasad V. Bharatam |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Reaction mechanism Cytochrome Stereochemistry Metabolite Antitubercular Agents 010402 general chemistry Toxicology Hydrazide 01 natural sciences Catalysis 03 medical and health sciences chemistry.chemical_compound Cytochrome P-450 Enzyme System Biotransformation Isoniazid medicine Humans biology Drug discovery General Medicine 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology chemistry biology.protein Quantum Theory Thermodynamics Metabolic Networks and Pathways Protein Binding medicine.drug |
| Zdroj: | Chemical Research in Toxicology. 30:2060-2073 |
| ISSN: | 1520-5010 0893-228X |
| Popis: | Hydrazide group (−C(O)–NH–NH2) is considered as a structural alert in the drug discovery process because the biotransformation chemistry of this group leads to the generation of toxic radical intermediates. The most important antitubercular drug isoniazid (INH) carries the hydrazide group. The toxicity of INH has been attributed to the protein adduct formation involving isonicotinoyl radical. However, the structures of reactive metabolites (RMs) and metabolite intermediate complexes (MICs), as well as the reaction mechanism for the formation and fate of RMs/MICs, have not been established. This report provides a detailed account of the biotransformation of INH by cytochromes using quantum chemical (QC) methods. Two cycles of cytochrome catalysis are involved in the formation of the most important RM, isonicotinoyl radical. The first cycle requires ∼11 kcal/mol barrier on the oxidation pathway involving the formation of the RM isonicotinoyldiazene. The second cycle involves a barrier of ∼7 kcal/mol for the... |
| Databáze: | OpenAIRE |
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