posted on 2021-04-21, 18:35authored byJunhao Li, Yue Chen, Yun Tang, Weihua Li, Yaoquan Tu
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.