Lo Rabindranath, Ganguly Bishwajit
Computation and Simulation Unit (Analytical Discipline and Centralized Instrument Facility), CSIR-Central Salt & Marine Chemicals Research Institute, Bhavnagar, Gujarat, India-364 002.
Mol Biosyst. 2014 Jul 29;10(9):2368-83. doi: 10.1039/c4mb00083h.
Organophosphorus nerve agents are highly toxic compounds which strongly inhibit acetylcholinesterase (AChE) in the blood and in the central nervous system (CNS). Tabun is one of the highly toxic organophosphorus (OP) compounds and is resistant to many oxime drugs formulated for the reactivation of AChE. The reactivation mechanism of tabun-conjugated AChE with various drugs has been examined with density functional theory and ab initio quantum chemical calculations. The presence of a lone-pair located on the amidic group resists the nucleophilic attack at the phosphorus center of the tabun-conjugated AChE. We have shown that the newly designed drug candidate N-(pyridin-2-yl)hydroxylamine, at the MP2/6-31+G*//M05-2X/6-31G* level in the aqueous phase with the polarizable continuum solvation model (PCM), is more effective in reactivating the tabun-conjugated AChE than typical oxime drugs. The rate determining activation barrier with N-(pyridin-2-yl)hydroxylamine was found to be ∼1.7 kcal mol(-1), which is 7.2 kcal mol(-1) lower than the charged oxime trimedoxime (one of the most efficient reactivators in tabun poisonings). The greater nucleophilicity index (ω(-)) and higher CHelpG charge of pyridinylhydroxylamine compared to TMB4 support this observation. Furthermore, we have also examined the reactivation process of tabun-inhibited AChE with some other bis-quaternary oxime drug candidates such as methoxime (MMB4) and obidoxime. The docking analysis suggests that charged bis-quaternary pyridinium oximes have greater binding affinity inside the active-site gorge of AChE compared to the neutral pyridinylhydroxylamine. The peripheral ligand attached to the neutral pyridinylhydroxylamine enhanced the binding with the aromatic residues in the active-site gorge of AChE through effective π-π interactions. Steered molecular dynamics (SMD) simulations have also been performed with the charged oxime (TMB4) and the neutral hydroxylamine. From protein-drug interaction parameters (rupture force profiles, hydrogen bonds, hydrophobic interactions), geometry and the orientation of the drug candidates, the hydroxylamine is suggested to orchestrate the reactivation process better than TMB4. Furthermore, the calculated log P values show the effective penetration of the neutral drug candidate through the blood-brain barrier. The toxicity measurements and the IC50 values (a measure of the intrinsic affinity toward AChE) suggest that the pyridinylhydroxylamine compound could have similar toxic behavior compared to the prototype oxime antidotes used for reactivation purposes. The newly designed pyridinylhydroxylamine drug candidate can be an effective antidote both kinetically and structurally to reactivate the tabun-inhibited enzyme.
有机磷神经毒剂是剧毒化合物，能强烈抑制血液和中枢神经系统（CNS）中的乙酰胆碱酯酶（AChE）。塔崩是剧毒有机磷（OP）化合物之一，对许多用于使AChE重新活化的肟类药物具有抗性。已用密度泛函理论和从头算量子化学计算研究了塔崩共轭AChE与各种药物的重新活化机制。位于酰胺基团上的孤对电子的存在阻碍了对塔崩共轭AChE磷中心的亲核攻击。我们已经表明，新设计的候选药物N-（吡啶-2-基）羟胺，在水相中采用极化连续介质溶剂化模型（PCM），在MP2/6-31+G*//M05-2X/6-31G*水平下，比典型的肟类药物更有效地重新活化塔崩共轭AChE。发现N-（吡啶-2-基）羟胺的速率决定活化能垒约为1.7 kcal mol⁻¹，比带电荷的肟双复磷（塔崩中毒中最有效的重新活化剂之一）低7.2 kcal mol⁻¹。与TMB4相比，吡啶基羟胺具有更大的亲核性指数（ω⁻）和更高的CHelpG电荷，支持了这一观察结果。此外，我们还研究了塔崩抑制的AChE与其他一些双季铵肟类候选药物如甲肟（MMB4）和双复磷的重新活化过程。对接分析表明，与中性吡啶基羟胺相比，带电荷的双季铵吡啶鎓肟在AChE活性位点峡谷内具有更大的结合亲和力。连接到中性吡啶基羟胺上的外围配体通过有效的π-π相互作用增强了与AChE活性位点峡谷中芳香族残基的结合。还对带电荷的肟（TMB4）和中性羟胺进行了引导分子动力学（SMD）模拟。从蛋白质-药物相互作用参数（断裂力曲线、氢键、疏水相互作用）、候选药物的几何形状和取向来看，羟胺比TMB4更能协调重新活化过程。此外，计算得到的log P值表明中性候选药物能有效穿透血脑屏障。毒性测量和IC50值（衡量对AChE的内在亲和力的指标）表明，吡啶基羟胺化合物与用于重新活化目的的原型肟解毒剂相比可能具有相似的毒性行为。新设计的吡啶基羟胺候选药物在动力学和结构上都可以是重新活化塔崩抑制酶的有效解毒剂。
