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Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4: Insight from Computational Studies
[Image: see text] Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of ∼50% clinically used drugs. Midazolam (MDZ) is a commonly used sedative drug and serves as a marker substrate for the CYP3A4 activity assessment. MDZ is metabolized by CYP3A4 to two hydroxylation products, 1′-O...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278384/ https://www.ncbi.nlm.nih.gov/pubmed/33884878 http://dx.doi.org/10.1021/acs.jcim.1c00266 |
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author | Li, Junhao Chen, Yue Tang, Yun Li, Weihua Tu, Yaoquan |
author_facet | Li, Junhao Chen, Yue Tang, Yun Li, Weihua Tu, Yaoquan |
author_sort | Li, Junhao |
collection | PubMed |
description | [Image: see text] Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of ∼50% clinically used drugs. Midazolam (MDZ) is a commonly used sedative drug and serves as a marker substrate for the CYP3A4 activity assessment. MDZ is metabolized by CYP3A4 to two hydroxylation products, 1′-OH-MDZ and 4-OH-MDZ. It has been reported that the ratio of 1′-OH-MDZ and 4-OH-MDZ is dependent on the MDZ concentration, which reflects the homotropic cooperative behavior in MDZ metabolism by CYP3A4. Here, we used quantum chemistry (QC), molecular docking, conventional molecular dynamics (cMD), and Gaussian accelerated molecular dynamics (GaMD) approaches to investigate the mechanism of the interactions between CYP3A4 and MDZ. QC calculations suggest that C1′ is less reactive for hydroxylation than C4, which is a pro-chirality carbon. However, the 4-OH-MDZ product is likely to be racemic due to the chirality inversion in the rebound step. The MD simulation results indicate that MDZ at the peripheral allosteric site is not stable and the binding modes of the MDZ molecules at the productive site are in line with the experimental observations. |
format | Online Article Text |
id | pubmed-8278384 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-82783842021-07-14 Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4: Insight from Computational Studies Li, Junhao Chen, Yue Tang, Yun Li, Weihua Tu, Yaoquan J Chem Inf Model [Image: see text] Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of ∼50% clinically used drugs. Midazolam (MDZ) is a commonly used sedative drug and serves as a marker substrate for the CYP3A4 activity assessment. MDZ is metabolized by CYP3A4 to two hydroxylation products, 1′-OH-MDZ and 4-OH-MDZ. It has been reported that the ratio of 1′-OH-MDZ and 4-OH-MDZ is dependent on the MDZ concentration, which reflects the homotropic cooperative behavior in MDZ metabolism by CYP3A4. Here, we used quantum chemistry (QC), molecular docking, conventional molecular dynamics (cMD), and Gaussian accelerated molecular dynamics (GaMD) approaches to investigate the mechanism of the interactions between CYP3A4 and MDZ. QC calculations suggest that C1′ is less reactive for hydroxylation than C4, which is a pro-chirality carbon. However, the 4-OH-MDZ product is likely to be racemic due to the chirality inversion in the rebound step. The MD simulation results indicate that MDZ at the peripheral allosteric site is not stable and the binding modes of the MDZ molecules at the productive site are in line with the experimental observations. American Chemical Society 2021-04-22 2021-05-24 /pmc/articles/PMC8278384/ /pubmed/33884878 http://dx.doi.org/10.1021/acs.jcim.1c00266 Text en © 2021 The Authors. Published by American Chemical Society Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Li, Junhao Chen, Yue Tang, Yun Li, Weihua Tu, Yaoquan Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4: Insight from Computational Studies |
title | Homotropic Cooperativity of Midazolam Metabolism by
Cytochrome P450 3A4: Insight from Computational Studies |
title_full | Homotropic Cooperativity of Midazolam Metabolism by
Cytochrome P450 3A4: Insight from Computational Studies |
title_fullStr | Homotropic Cooperativity of Midazolam Metabolism by
Cytochrome P450 3A4: Insight from Computational Studies |
title_full_unstemmed | Homotropic Cooperativity of Midazolam Metabolism by
Cytochrome P450 3A4: Insight from Computational Studies |
title_short | Homotropic Cooperativity of Midazolam Metabolism by
Cytochrome P450 3A4: Insight from Computational Studies |
title_sort | homotropic cooperativity of midazolam metabolism by
cytochrome p450 3a4: insight from computational studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278384/ https://www.ncbi.nlm.nih.gov/pubmed/33884878 http://dx.doi.org/10.1021/acs.jcim.1c00266 |
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