ArticleJournal of chemical information and modeling2021
Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4: Insight from Computational Studies.
Article in Journal of chemical information and modeling, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 28 citations in OpenAlex.
- Effect of Remimazolam vs Midazolam on Early Postoperative Cognitive Recovery in Elderly Patients Undergoing Dental Extraction: A Prospective Randomized Controlled Study.Drug design, development and therapy · 2024Trial
- Effects of TPA023B, an α2/3/5GABAPsychopharmacology · 2026Article
- Benzodiazepine-resistant epilepsy: unraveling molecular mechanisms and developing multimodal therapeutic strategies.Frontiers in neurology · 2025Review
- Elucidating the Mechanism of Metabolism of Cannabichromene by Human Cytochrome P450s.Journal of natural products · 2024Article
- Article
- Hepatic CYP3A4 Enzyme Compensatively Maintains Endogenous Geranylgeranoic Acid Levels inMetabolites · 2022Article
- Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress.Antioxidants (Basel, Switzerland) · 2021Article
- Differential Impact of Severity and Duration ofFrontiers in cellular neuroscience · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.