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

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

QC 20210629
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.

Chen, YueEast China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China. (författare)
Tang, YunEast China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China. (författare)
Li, WeihuaEast China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China. (författare)
Tu, YaoquanKTH,Teoretisk kemi och biologi(Swepub:kth)u1kuh2ie (författare)
KTHTeoretisk kemi och biologi (creator_code:org_t)

Ingår i:Journal of Chemical Information and Modeling: American Chemical Society (ACS)61:5, s. 2418-24261549-95961549-960X

Av författaren/redakt...: Li, Junhao; Chen, Yue; Tang, Yun; Li, Weihua; Tu, Yaoquan

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