Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef, 62514, Egypt.
Departamento de Química, Universidad Autónoma de Madrid, Módulo 13, Campus de Excelencia UAM-CSIC Cantoblanco, Madrid, Spain and Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Org Biomol Chem. 2020 May 6;18(17):3334-3345. doi: 10.1039/d0ob00529k.
The mechanism-based inactivation (MBI) of P450 by paroxetine was investigated by computational analysis. The drug-enzyme interactions were figured out through studying energy profiles of three competing mechanisms. The potency of paroxetine as P450's inhibitor was estimated based on the availability of two active sites for the MBI in the paroxetine structure. The inactivation by the amino site of paroxetine mainly proceeds via the hydrogen atom transfer pathway because of the lower energy demand of its rate determining step. In addition, the low-spin state is the predominant route in the MBI at the methylenedioxo active site as a result of being rebound barrier-free mechanism. Our comparative investigation showed that inactivation at the secondary amine is thermodynamically more favorable because of the lower energy barrier of the dehydration mechanism of the hydroxylated paroxetine complex than its methylenedioxo counterpart. The results of docking analysis coincided with the outputs of DFT calculations since the docking pose with the lowest binding affinity is that for conformation with polar interaction between the amino group of paroxetine and the oxo moiety of P450's active site. Assessment of the molecular dynamics simulations trajectories revealed the favorable interaction of paroxetine with P450.
通过计算分析研究了帕罗西汀对 P450 的基于机制的失活（MBI）。通过研究三种竞争机制的能量分布，确定了药物-酶相互作用。基于帕罗西汀结构中存在两个用于 MBI 的活性部位，估计了帕罗西汀作为 P450 抑制剂的效力。由于其速率决定步骤的能量需求较低，帕罗西汀的氨基部位的失活主要通过氢原子转移途径进行。此外，由于再结合无阻碍机制，在亚甲基二氧活性部位的 MBI 中低自旋态是主要途径。我们的比较研究表明，由于羟基化帕罗西汀复合物的脱水机制的能量势垒低于其亚甲基二氧对应物，因此在二级胺上的失活在热力学上更为有利。对接分析的结果与 DFT 计算的结果一致，因为具有最低结合亲和力的对接构象是帕罗西汀的氨基与 P450 活性部位的氧部分之间具有极性相互作用的构象。评估分子动力学模拟轨迹表明帕罗西汀与 P450 之间存在有利的相互作用。
