Lo Rabindranath, Chandar Nellore Bhanu, Kesharwani Manoj K, Jain Aastha, Ganguly Bishwajit
Computation and Simulation Unit (Analytical Discipline and Centralized Instrument Facility), CSIR-Central Salt & Marine Chemicals Research Institute, Bhavnagar, Gujarat, India.
PLoS One. 2013 Dec 2;8(12):e79591. doi: 10.1371/journal.pone.0079591. eCollection 2013.
We have examined the reactivation mechanism of the tabun-conjugated AChE with various drugs using density functional theory (DFT) and post-Hartree-Fock methods. The electronic environments and structural features of neutral oximes (deazapralidoxime and 3-hydroxy-2-pyridinealdoxime) and charged monopyridinium oxime (2-PAM) and bispyridinium oxime (Ortho-7) are different, hence their efficacy varies towards the reactivation process of tabun-conjugated AChE. The calculated potential energy surfaces suggest that a monopyridinium reactivator is less favorable for the reactivation of tabun-inhibited AChE compared to a bis-quaternary reactivator, which substantiates the experimental study. The rate determining barrier with neutral oximes was found to be ∼2.5 kcal/mol, which was ∼5.0 kcal/mol lower than charged oxime drugs such as Ortho-7. The structural analysis of the calculated geometries suggest that the charged oximes form strong O(…)H and N(…)H hydrogen bonding and C-H(…)π non-bonding interaction with the tabun-inhibited enzyme to stabilize the reactant complex compared to separated reactants, which influences the activation barrier. The ability of neutral drugs to cross the blood-brain barrier was also found to be superior to charged antidotes, which corroborates the available experimental observations. The calculated activation barriers support the superiority of neutral oximes for the activation of tabun-inhibited AChE compared to charged oximes. However, they lack effective interactions with their peripheral sites. Docking studies revealed that the poor binding affinity of simple neutral oxime drugs such as 3-hydroxy-2-pyridinealdoxime inside the active-site gorge of AChE was significantly augmented with the addition of neutral peripheral units compared to conventional charged peripheral sites. The newly designed oxime drug 2 appears to be an attractive candidate as efficient antidote to kinetically and structurally reactivate the tabun-inhibited enzyme.
我们使用密度泛函理论（DFT）和后哈特里 - 福克方法研究了各种药物对塔崩缀合乙酰胆碱酯酶（AChE）的重新激活机制。中性肟（脱氮解磷定和3 - 羟基 - 2 - 吡啶醛肟）以及带电荷的单吡啶鎓肟（2 - PAM）和双吡啶鎓肟（Ortho - 7）的电子环境和结构特征不同，因此它们对塔崩缀合AChE的重新激活过程的功效也有所不同。计算得到的势能面表明，与双季铵盐重新激活剂相比，单吡啶鎓重新激活剂对塔崩抑制的AChE的重新激活不太有利，这证实了实验研究。发现中性肟的速率决定势垒约为2.5千卡/摩尔，比带电荷的肟类药物如Ortho - 7低约5.0千卡/摩尔。对计算得到的几何结构进行结构分析表明，与分离的反应物相比，带电荷的肟与塔崩抑制的酶形成强的O（…）H和N（…）H氢键以及C - H（…）π非键相互作用以稳定反应物复合物，这影响了活化势垒。还发现中性药物穿过血脑屏障的能力优于带电荷的解毒剂，这证实了现有的实验观察结果。计算得到的活化势垒支持中性肟在激活塔崩抑制的AChE方面优于带电荷的肟。然而，它们与外周位点缺乏有效的相互作用。对接研究表明，与传统的带电荷外周位点相比，添加中性外周单元后，简单中性肟药物如3 - 羟基 - 2 - 吡啶醛肟在AChE活性位点峡谷内的结合亲和力显著增强。新设计的肟类药物2似乎是一种有吸引力的候选药物，可作为有效解毒剂在动力学和结构上重新激活塔崩抑制的酶。
