Chadha Nidhi, Tiwari Anjani K, Kumar Vikas, Lal Sangeeta, Milton Marilyn D, Mishra Anil K
a Division of Cyclotron and Radiopharmaceutical Sciences , Institute of Nuclear Medicine and Allied Sciences , Brig. S. K. Mazumdar Road, Delhi 110054 , India.
J Biomol Struct Dyn. 2015;33(5):978-90. doi: 10.1080/07391102.2014.921793. Epub 2014 May 29.
Neuropathological cascades leading to reduced cholinergic transmission in Alzheimer's disease led to development of AChE-inhibitors. Although lethal dose of some inhibitors cause interruption with AChE mediated mechanism but reversible AChE inhibitors can assist in protection from inhibition of AChE and hence in an aim to probe potential molecules as anticholinesterase and as reactivators, computationally structure-based approach has been exploited in this work for designing new 2-amino-3-pyridoixime-dipeptides conjugates. We have combined MD simulations with flexible ligand docking approach to determine binding specificity of 2-amino-3-pyridoixime dipeptides towards AChE (PDB 2WHP). PAS residues are found to be responsible for oxime-dipeptides binding along with π-π interactions with Trp86 and Tyr286, hydrogen bonding with side chains of Asp74 and Tyr341 (Gscore -10.801 and MM-GBSA free energy -34.89 kcal/mol). The docking results depicted complementary multivalent interactions along with good binding affinity as predicted from MM-GBSA analysis. The 2-amino-3-pyridoxime-(Arg-Asn) AChE systems subjected to MD simulations under explicit solvent systems with NPT and NVT ensemble. MD simulations uncovered dynamic behavior of 2-amino-3-pyridoxime-(Arg-Asn) and exposed its mobile nature and competence to form strong long range-order contacts towards active site residues to approach inhibited serine residue and facilitated via large contribution from hydrogen bonding and water bridges along with slow and large movements of adjacent important residues. In an effort to evaluate the complete potential surface profile, 2-amino-3-pyridoxime induced reactivation pathway of sarin-serine adduct has been investigated by the DFT approach at the vacuum MO6/6-311G (d, p) level along with the Poisson-Boltzmann solvation model and found to be of relatively low energy barrier. The pKa evaluation has revealed the major deprotonated 2-amino-3-pyridoixime species having pKa of 6.47 and hence making 2-amino-3-pyridoxime-(Arg-Asn) potential anticholinesterase and reactivator for AChE under the physiological pH.
导致阿尔茨海默病中胆碱能传递减少的神经病理学级联反应促使了乙酰胆碱酯酶抑制剂的研发。尽管某些抑制剂的致死剂量会干扰乙酰胆碱酯酶介导的机制，但可逆性乙酰胆碱酯酶抑制剂有助于防止乙酰胆碱酯酶受到抑制，因此，为了探索作为抗胆碱酯酶和再活化剂的潜在分子，本研究采用了基于结构的计算方法来设计新的2-氨基-3-吡啶肟二肽缀合物。我们将分子动力学模拟与柔性配体对接方法相结合，以确定2-氨基-3-吡啶肟二肽对乙酰胆碱酯酶（PDB 2WHP）的结合特异性。发现PAS残基负责肟二肽的结合，以及与Trp86和Tyr286的π-π相互作用、与Asp74和Tyr341侧链的氢键作用（Gscore -10.801和MM-GBSA自由能-34.89 kcal/mol）。对接结果显示了互补的多价相互作用以及如MM-GBSA分析所预测的良好结合亲和力。2-氨基-3-吡啶肟-（精氨酸-天冬酰胺）乙酰胆碱酯酶系统在具有NPT和NVT系综的显式溶剂系统下进行分子动力学模拟。分子动力学模拟揭示了2-氨基-3-吡啶肟-（精氨酸-天冬酰胺）的动态行为，展现了其可移动性以及与活性位点残基形成强远程有序接触的能力，从而接近被抑制的丝氨酸残基，这一过程通过氢键和水桥的大量贡献以及相邻重要残基的缓慢且大幅度移动得以促进。为了评估完整的势能面轮廓，采用密度泛函理论方法在真空MO6/6-311G(d, p)水平以及泊松-玻尔兹曼溶剂化模型下研究了2-氨基-3-吡啶肟诱导的沙林-丝氨酸加合物的再活化途径，发现其能垒相对较低。pKa评估表明主要的去质子化2-氨基-3-吡啶肟物种的pKa为6.47，因此使2-氨基-3-吡啶肟-（精氨酸-天冬酰胺）在生理pH下具有作为乙酰胆碱酯酶的潜在抗胆碱酯酶和再活化剂的特性。
