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Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5

CYP 3A4 and CYP 3A5 are two important members of the human cytochrome P450 family. Although their overall structures are similar, the local structures of the active site are different, which directly leads to obvious individual differences in drug metabolic efficacy and toxicity. In this work, midaz...

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Autores principales: Liu, Shuhui, Zheng, Qingchuan, Bai, Fuquan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10574787/
https://www.ncbi.nlm.nih.gov/pubmed/37836743
http://dx.doi.org/10.3390/molecules28196900
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author Liu, Shuhui
Zheng, Qingchuan
Bai, Fuquan
author_facet Liu, Shuhui
Zheng, Qingchuan
Bai, Fuquan
author_sort Liu, Shuhui
collection PubMed
description CYP 3A4 and CYP 3A5 are two important members of the human cytochrome P450 family. Although their overall structures are similar, the local structures of the active site are different, which directly leads to obvious individual differences in drug metabolic efficacy and toxicity. In this work, midazolam (MDZ) was selected as the probe substrate, and its interaction with two proteins, CYP 3A4 and CYP 3A5, was studied by molecular dynamics simulation (MD) along with the calculation of the binding free energy. The results show that two protein–substrate complexes have some similarities in enzyme–substrate binding; that is, in both complexes, Ser119 forms a high occupancy hydrogen bond with MDZ, which plays a key role in the stability of the interaction between MDZ and the enzymes. However, the complex formed by CYP 3A4 and MDZ is more stable, which may be attributed to the sandwich structure formed by the fluorophenyl group of the substrate with Leu216 and Leu482. Our study interprets the binding differences between two isoform–substrate complexes and reveals a structure–function relationship from the atomic perspective, which is expected to provide a theoretical basis for accurately measuring the effectiveness and toxicity of drugs for individuals in the era of precision medicine.
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spelling pubmed-105747872023-10-14 Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5 Liu, Shuhui Zheng, Qingchuan Bai, Fuquan Molecules Article CYP 3A4 and CYP 3A5 are two important members of the human cytochrome P450 family. Although their overall structures are similar, the local structures of the active site are different, which directly leads to obvious individual differences in drug metabolic efficacy and toxicity. In this work, midazolam (MDZ) was selected as the probe substrate, and its interaction with two proteins, CYP 3A4 and CYP 3A5, was studied by molecular dynamics simulation (MD) along with the calculation of the binding free energy. The results show that two protein–substrate complexes have some similarities in enzyme–substrate binding; that is, in both complexes, Ser119 forms a high occupancy hydrogen bond with MDZ, which plays a key role in the stability of the interaction between MDZ and the enzymes. However, the complex formed by CYP 3A4 and MDZ is more stable, which may be attributed to the sandwich structure formed by the fluorophenyl group of the substrate with Leu216 and Leu482. Our study interprets the binding differences between two isoform–substrate complexes and reveals a structure–function relationship from the atomic perspective, which is expected to provide a theoretical basis for accurately measuring the effectiveness and toxicity of drugs for individuals in the era of precision medicine. MDPI 2023-10-01 /pmc/articles/PMC10574787/ /pubmed/37836743 http://dx.doi.org/10.3390/molecules28196900 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Shuhui
Zheng, Qingchuan
Bai, Fuquan
Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5
title Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5
title_full Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5
title_fullStr Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5
title_full_unstemmed Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5
title_short Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5
title_sort differences of atomic-level interactions between midazolam and two cyp isoforms 3a4 and 3a5
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10574787/
https://www.ncbi.nlm.nih.gov/pubmed/37836743
http://dx.doi.org/10.3390/molecules28196900
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