Mechanistic studies of cytochrome P450 3A4 time-dependent inhibition using two cysteine-targeting electrophiles was written by Barr, John T.;Wang, Zhican;Min, Xiaoshan;Wienkers, Henry J.;Rock, Brooke M.;Rock, Dan A.;Wienkers, Larry C.. And the article was included in Drug Metabolism & Disposition in 2020.Electric Literature of C6H6N4 This article mentions the following:
Experiments designed to identify the mechanism of cytochrome P 450 inactivation are critical to drug discovery. Small mols. irreversibly inhibit P 450 enzymic activity via two primary mechanisms: apoprotein adduct formation or heme modification. Understanding the interplay between chem. structures of reactive electrophiles and the impact on CYP3A4 structure and function can ultimately provide insights into drug design to minimize P 450 inactivation. The compound’s effect on (1) enzymic activity, (2) carbon monoxide (CO) binding capacity, (3) intact heme content, and (4) protein conformation were measured. Results showed that PM had a large time-dependent loss of enzyme activity, whereas PIA did not. The differential effect on enzymic activity between PM and PIA was mirrored in the CO binding data. Despite disruption of CO binding, neither compound affected the heme concentrations, inferring there was no destruction or alkylation of the heme. Lastly, differential scanning fluorescence showed PM-treated CYP3A4 caused a shift in the onset temperature required to induce protein aggregation, which was not observed for CYP3A4 treated with PIA. In conclusion, alkylation of CYP3A4 apoprotein can have a variable impact on catalytic activity, CO binding, and protein conformation that may be compound-dependent. These results highlight the need for careful interpretation of exptl. results aimed at characterizing the nature of P 450 enzyme inactivation. In the experiment, the researchers used many compounds, for example, 1H-Benzo[d][1,2,3]triazol-1-amine (cas: 1614-12-6Electric Literature of C6H6N4).
1H-Benzo[d][1,2,3]triazol-1-amine (cas: 1614-12-6) belongs to triazole derivatives. The many free lone pairs in triazoles make them useful as coordination compounds, although not typically as haptic ligands.Triazole heterocyclic structures are found to form many weak nonbond interactions with the receptors and enzymes in biological systems.Electric Literature of C6H6N4
Referemce:
1,2,3-Triazole – Wikipedia,
Triazoles – an overview | ScienceDirect Topics