Mitrasinovic Petar M
Center for Biophysical and Chemical Research, Belgrade Institute of Science and Technology, Belgrade, Serbia.
J Biomol Struct Dyn. 2022;40(20):9713-9723. doi: 10.1080/07391102.2021.1932603. Epub 2021 Jun 1.
Cytochrome P450 3A4 (CYP3A4) is the most versatile enzyme involved in drug metabolism. The time-dependent inhibition of CYP3A4 by acacetin, apigenin, chrysin, and pinocembrin was experimentally detected, but not entirely elaborated so far. Thus, a two-level QM/MM (Quantum Mechanics/Molecular Mechanics) model is developed to yield insights into the receptor-flavonoid recognition at the molecular scale. Active site residues and the flavonoid are modelled using SCC-DFTB-D (QM level), while the rest of the complex is treated using AMBER force field (MM level). QM/MM binding free energies are well correlated with experimental data, indicating the largest inhibitory effect of chrysin on enzyme activity at a submicromolar concentration. Consequently, quercetin (QUE) and flavopiridol (FLP) are observed as representative examples of structurally different flavonoids. The inhibition parameters for QUE and FLP are evaluated using the well-calibrated QM/MM strategy, thereby aiding to quantitatively conceive the functional behavior of the whole family of flavonoids. A kinetic threshold for further assessment of the drug-drug interactions underlying the time-dependent inhibition of CYP3A4 by flavonoids is explored.Communicated by Ramaswamy H. Sarma.
细胞色素P450 3A4（CYP3A4）是参与药物代谢的最具通用性的酶。实验检测到了刺槐素、芹菜素、白杨素和松属素对CYP3A4的时间依赖性抑制作用，但迄今为止尚未完全阐明。因此，开发了一种两级量子力学/分子力学（QM/MM）模型，以在分子尺度上深入了解受体-黄酮类化合物的识别。活性位点残基和黄酮类化合物使用SCC-DFTB-D（量子力学水平）进行建模，而复合物的其余部分则使用AMBER力场（分子力学水平）进行处理。QM/MM结合自由能与实验数据高度相关，表明白杨素在亚微摩尔浓度下对酶活性的抑制作用最大。因此，观察到槲皮素（QUE）和黄酮哌啶醇（FLP）作为结构不同的黄酮类化合物的代表实例。使用经过良好校准的QM/MM策略评估了QUE和FLP的抑制参数，从而有助于定量地理解整个黄酮类化合物家族的功能行为。探索了一个动力学阈值，用于进一步评估黄酮类化合物对CYP3A4时间依赖性抑制作用背后的药物-药物相互作用。由拉马斯瓦米·H·萨尔马传达。
