How does multiple substrate binding lead to substrate inhibition of CYP2D6 metabolizing dextromethorphan? A theoretical study.
Phys Chem Chem Phys
; 25(6): 5164-5173, 2023 Feb 08.
Article
em En
| MEDLINE
| ID: mdl-36723118
ABSTRACT
CYP2D6 is one of the most important metalloenzymes involved in the biodegradation of many drug molecules in the human body. It has been found that multiple substrate binding can lead to substrate inhibition of CYP2D6 metabolizing dextromethorphan (DM), but the corresponding theoretical mechanism is rarely reported. Therefore, we chose DM as the probe and performed molecular dynamics simulations and quantum mechanical calculations on CYP2D6-DM systems to investigate the mechanism of how the multiple substrate binding leads to the substrate inhibition of CYP2D6 metabolizing substrates. According to our results, three gate residues (Arg221, Val374, and Phe483) for the catalytic pocket are determined. We also found that the multiple substrate binding can lead to substrate inhibition by reducing the stability of CYP2D6 binding DM and increasing the reactive activation energy of the rate-determining step. Our findings would help to understand the substrate inhibition of CYP2D6 metabolizing the DM and enrich the knowledge of the drug-drug interactions for the cytochrome P450 superfamily.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Citocromo P-450 CYP2D6
/
Dextrometorfano
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article