Central Salt & Marine Chemicals Research Institute, Bhavnagar, Gujarat, India.
Acta Pharmacol Sin. 2010 Mar;31(3):313-28. doi: 10.1038/aps.2009.193. Epub 2010 Feb 8.
To performe a time-dependent topographical delineation of protein-drug interactions to gain molecular insight into the supremacy of Ortho-7 over HI-6 in reactivating tabun-conjugated mouse acetylcholinesterase (mAChE).
We conducted all-atom steered molecular dynamics simulations of the two protein-drug complexes. Through a host of protein-drug interaction parameters (rupture force profiles, hydrogen bonds, water bridges, hydrophobic interactions), geometrical, and orientation ordering of the drugs, we monitored the enzyme's response during the release of the drugs from its active-site.
The results show the preferential binding of the drugs with the enzyme. The pyridinium ring of HI-6 shows excellent complementary binding with the peripheral anionic site, whereas one of two identical pyridinium rings of Ortho-7 has excellent binding compatibility in the enzyme active-site where it can orchestrate the reactivation process. We found that the active pyridinium ring of HI-6 undergoes a complete turn along the active site axis, directed away from the active-site region during the course of the simulation.
Due to excellent cooperative binding of Ortho-7, as rendered by several cation-pi interactions with the active-site gorge of the enzyme, Ortho-7 may be a more efficient reactivator than HI-6. Our work supports the growing body of evidence that the efficacy of the drugs is due to the differential bindings of the oximes with AChE and can aid to the rational design of oxime drugs.
对蛋白-药物相互作用进行时变的拓扑描述，深入了解 Ortho-7 在重新激活与 tabun 结合的鼠乙酰胆碱酯酶（mAChE）方面优于 HI-6 的原因。
我们对两个蛋白-药物复合物进行了全原子导向分子动力学模拟。通过一系列蛋白-药物相互作用参数（断裂力谱、氢键、水桥、疏水相互作用）、药物的几何形状和取向有序性，我们监测了酶在药物从活性部位释放过程中的反应。
结果表明药物与酶的优先结合。HI-6 的吡啶环与外周阴离子部位表现出极好的互补结合，而 Ortho-7 的两个相同吡啶环之一在酶活性部位具有极好的结合兼容性，它可以协调重激活过程。我们发现 HI-6 的活性吡啶环在模拟过程中沿着活性部位轴完全翻转，远离活性部位区域。
由于 Ortho-7 与酶的活性部位峡谷之间存在几个阳离子-π 相互作用，表现出极好的协同结合，因此 Ortho-7 可能比 HI-6 更有效。我们的工作支持越来越多的证据表明，药物的疗效是由于肟与 AChE 的不同结合，可以帮助合理设计肟类药物。
