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Homotropic Cooperat...
Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4 : Insight from Computational Studies
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- Li, Junhao (author)
- KTH,Teoretisk kemi och biologi
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- Chen, Yue (author)
- East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China.
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- Tang, Yun (author)
- East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China.
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- Li, Weihua (author)
- East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China.
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- Tu, Yaoquan (author)
- KTH,Teoretisk kemi och biologi
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(creator_code:org_t)
- 2021-04-22
- 2021
- English.
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In: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 61:5, s. 2418-2426
- Related links:
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https://doi.org/10.1...
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https://pubs.acs.org...
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https://urn.kb.se/re...
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Abstract
Subject headings
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- Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of similar to 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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