Mechanism of the Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4: Insight from Computational Studies

• Midazolam (MDZ) is a commonly used drug and is metabolized by cytochrome P450 3A4 (CYP3A4). It has been reported that the ratio of the hydroxylation products, 1'-OH-MDZ/4-OH-MDZ, is dependent on the MDZ concentration, which reflects that there exists the homotropic cooperative behavior in the CYP3A4-mediated hydroxylation of MDZ. Here, we used quantum chemistry (QC), molecular docking, conventional molecular dynamics (cMD) simulation, and Gaussian accelerated molecular dynamics (GaMD) simulation approaches to investigate the mechanism of the interactions between CYP3A4 and MDZ. Our study suggests that the H41 site, i.e. the pro-R center, is the most reactive site for the hydrogen abstraction, followed by the C1' site. However, the product 4-OH-MDZ is likely to be racemic due to the chirality inversion in the rebound step. We found that the allosteric site was not involved in the ligand cooperativity and the observation that there exists one or two MDZs in the productive site is in line with the experimental observations.

Ämnesord

NATURVETENSKAP  -- Biologi -- Annan biologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Other Biological Topics (hsv//eng)

Nyckelord

CYP3A4

homotropic cooperativity

midazolam

quantum chemistry

molecular dynamics

Biological Physics

Biologisk fysik

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