Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center "Kazan Scientific Center of the Russian Academy of Sciences", Arbuzov str., 8, 420088 Kazan, Russia.
Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Kosygin str. 4, 119334 Moscow, Russia.
Biomolecules. 2020 Nov 27;10(12):1608. doi: 10.3390/biom10121608.
Kinetic studies and molecular modeling of human acetylcholinesterase (AChE) inhibition by a fluorinated acetophenone derivative, 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (TFK), were performed. Fast reversible inhibition of AChE by TFK is of competitive type with = 5.15 nM. However, steady state of inhibition is reached slowly. Kinetic analysis showed that TFK is a slow-binding inhibitor (SBI) of type B with = 0.53 nM. Reversible binding of TFK provides a long residence time, = 20 min, on AChE. After binding, TFK acylates the active serine, forming an hemiketal. Then, disruption of hemiketal (deacylation) is slow. AChE recovers full activity in approximately 40 min. Molecular docking and MD simulations depicted the different steps. It was shown that TFK binds first to the peripheral anionic site. Then, subsequent slow induced-fit step enlarged the gorge, allowing tight adjustment into the catalytic active site. Modeling of interactions between TFK and AChE active site by QM/MM showed that the "isomerization" step of enzyme-inhibitor complex leads to a complex similar to substrate tetrahedral intermediate, a so-called "transition state analog", followed by a labile covalent intermediate. SBIs of AChE show prolonged pharmacological efficacy. Thus, this fluoroalkylketone intended for neuroimaging, could be of interest in palliative therapy of Alzheimer's disease and protection of central AChE against organophosphorus compounds.
对氟代苯乙酮衍生物 1-(3-叔丁基苯基)-2,2,2-三氟乙酮（TFK）对人乙酰胆碱酯酶（AChE）抑制的动力学研究和分子建模进行了研究。TFK 对 AChE 的快速可逆抑制呈竞争性， = 5.15 nM。然而，抑制的稳态是缓慢达到的。动力学分析表明，TFK 是一种 B 型慢结合抑制剂（SBI）， = 0.53 nM。TFK 的可逆结合提供了在 AChE 上的长停留时间， = 20 min。结合后，TFK 酰化活性丝氨酸，形成半缩醛。然后，半缩醛的破坏（脱酰基化）很慢。AChE 在大约 40 分钟内恢复全部活性。分子对接和 MD 模拟描绘了不同的步骤。结果表明，TFK 首先结合到外周阴离子结合位点。然后，随后的缓慢诱导契合步骤扩大了峡谷，允许紧密调整进入催化活性位点。通过 QM/MM 对 TFK 和 AChE 活性位点之间的相互作用进行建模表明，酶-抑制剂复合物的“异构化”步骤导致类似于底物四面体中间物的复合物，即所谓的“过渡态类似物”，随后是不稳定的共价中间物。AChE 的 SBI 显示出延长的药理学疗效。因此，这种用于神经成像的氟烷基酮可能对阿尔茨海默病的姑息治疗和保护中枢 AChE 免受有机磷化合物的侵害具有重要意义。
