Mechanistic studies of the cationic binding pocket of CYP2C9 in vitro and in silico: metabolism of nonionizable analogs of tienilic acid
| Autor: | Sid D. Nelson, Hoa Le, Kevin A. Ford, S. Cyrus Khojasteh, Suzanne Tay, Peter M. Rademacher |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Stereochemistry
Carboxylic acid In silico Ticrynafen Pharmaceutical Science Alkylation In Vitro Techniques Substrate Specificity chemistry.chemical_compound Cations medicine Thiophene Humans Computer Simulation Carboxylate Diuretics Cytochrome P-450 CYP2C9 Pharmacology chemistry.chemical_classification biology Active site Uricosuric Agents Enzyme chemistry Tienilic acid biology.protein medicine.drug |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 42(11) |
| ISSN: | 1521-009X |
| Popis: | Tienilic acid (TA) is selectively oxidized at the C-5 position of the thiophene ring by the human liver enzyme cytochrome P450 2C9 (CYP2C9). This oxidation is mediated by the proximal positioning of the thiophene over the heme iron, which is proposed to be coordinated by an interaction of the TA carboxylic acid to a cationic binding pocket in the enzyme active site. In this study, we investigated how chemical modification of TA influences the bioactivation by CYP2C9. For this investigation, nine analogs of TA were chosen with substitutions on either side of the molecule. We tested three parameters, including CYP2C9 inhibition, metabolic profiling, and in silico docking. Of the 10 compounds tested, only two (TA and a noncarboxyl analog) resulted in competitive and time-dependent inhibition of CYP2C9. Metabolic profiling revealed a trend in which substitution of the carboxylate with nonionizable functional groups resulted in metabolic switching from oxidation of the aromatic ring to dealkylation reactions at the opposite side of the structure. The in silico modeling predicted an opposite binding orientation to that of TA for many analogs, including the 3-thenoyl regio-isomer analog, which contradicts previous models. Together these data show that disrupting interactions with the cationic binding pocket of CYP2C9 will impact the sites of metabolism and inhibition of the enzyme. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|