Chandar Nellore Bhanu, Lo Rabindranath, Ganguly Bishwajit
Computation and Simulation Unit (Analytical Discipline and Centralized Instrument Facility), CSIR-Central Salt & Marine Chemicals Research Institute, Bhavnagar, Gujarat 364 002, India; Academy of Scientific and Innovative Research, CSIR-CSMCRI, Bhavnagar, Gujarat 364 002, India.
Computation and Simulation Unit (Analytical Discipline and Centralized Instrument Facility), CSIR-Central Salt & Marine Chemicals Research Institute, Bhavnagar, Gujarat 364 002, India.
Chem Biol Interact. 2014 Nov 5;223:58-68. doi: 10.1016/j.cbi.2014.08.015. Epub 2014 Sep 9.
Dimethyl(pyridin-2-yl)sulfonium based oxime has been designed to reverse the aging process of organophosphorus inhibited AChE and to reactivate the aged-AChE adduct. We have employed DFT M05-2X/6-31G(∗) level of theory in aqueous phase with polarizable continuum solvation model (PCM) for the methylation of phosphonate ester monoanion of the soman-aged adduct. The calculated free energy of activation for the methyl transfer process from designed dimethyl(phenyl)sulfonium (1) to aged AChE-OP adduct occurs with a barrier of 31.4kcal/mol at M05-2X/6-31G(∗) level of theory, which is 6.4kcal/mol lower compared to the aging process signifies the preferential reversal process to recover the aged AChE-OP adduct. The pyridine ring containing alkylated sulfonium species, dimethyl(pyridin-2-yl)sulfonium (2), reduced the free energy of activation by 4.4kcal/mol compared to the previously reported alkylating agent N-methyl-2-methoxypyridinium species (A) for the alkylation of aged AChE-OP adduct. The free enzyme can be liberated from the inhibited acetylcholinesterase with the sulfonium compound decorated with an oxime group to avoid the administration of oxime drugs separately. The calculated potential energy surfaces show that the oxime based sulfonium compound (3) can effectively methylate the aged phosphonate ester monoanion of soman aged-adduct. The calculated global reactivity descriptors of the oxime 3 also shed light on this observation. To gain better understanding for protein drug interaction as well as the unbinding and conformational changes of the drug candidate in the active site of cholinesterase, steered molecular dynamics (SMD) simulation with 3 has been performed. Through a protein-drug interaction parameters (rupture force profiles, hydrogen bonds, hydrophobic interactions), geometrical and the orientation of drug-like candidate, the oxime 3 suggests to orchestrate the better reactivation process. The docking studies have been performed with 3 in the aged AChE and BChE to obtain the initial geometry of the SMD studies. The docking methods adopted in this study have been verified with the available crystal geometry of 1-methyl-2-(pentafluorobenzyloxyimino)pyridinium compound in aged soman inhibited human BChE (PDB code: 4B0P). The computational study suggests that the newly designed oxime is a potential candidate to reactivate the aged-AChE adduct.
基于二甲基（吡啶 - 2 - 基）锍的肟被设计用于逆转有机磷抑制的乙酰胆碱酯酶（AChE）的老化过程，并使老化的AChE加合物重新活化。我们采用密度泛函理论（DFT）的M05 - 2X/6 - 31G()水平，在水相中结合极化连续介质溶剂化模型（PCM），对梭曼老化加合物的膦酸酯单阴离子进行甲基化。在M05 - 2X/6 - 31G()理论水平下，计算得到从设计的二甲基（苯基）锍（1）到老化的AChE - OP加合物的甲基转移过程的活化自由能垒为31.4kcal/mol，与老化过程相比降低了6.4kcal/mol，这表明优先发生逆转过程以恢复老化的AChE - OP加合物。含吡啶环的烷基化锍物种二甲基（吡啶 - 2 - 基）锍（2），与先前报道的用于老化AChE - OP加合物烷基化的烷基化剂N - 甲基 - 2 - 甲氧基吡啶鎓物种（A）相比，活化自由能降低了4.4kcal/mol。可以用带有肟基的锍化合物将游离酶从受抑制的乙酰胆碱酯酶中释放出来，从而避免单独施用肟类药物。计算得到的势能面表明，基于肟的锍化合物（3）可以有效地甲基化梭曼老化加合物的老化膦酸酯单阴离子。肟3的计算全局反应性描述符也为这一观察结果提供了线索。为了更好地理解蛋白质 - 药物相互作用以及候选药物在胆碱酯酶活性位点的解离和构象变化，对3进行了引导分子动力学（SMD）模拟。通过蛋白质 - 药物相互作用参数（断裂力分布、氢键、疏水相互作用）、类药物候选物的几何形状和取向，肟3表明其能更好地协调重新活化过程。已对3在老化的AChE和BChE中进行对接研究，以获得SMD研究的初始几何结构。本研究中采用的对接方法已通过老化梭曼抑制的人BChE中1 - 甲基 - 2 - （五氟苄氧基肟基）吡啶鎓化合物的可用晶体几何结构（PDB代码：4B0P）进行了验证。计算研究表明，新设计的肟是使老化的AChE加合物重新活化的潜在候选物。
