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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Oxime-dipeptides as anticholinesterase, reactivator of phosphonylated-serine of AChE catalytic triad: probing the mechanistic insight by MM-GBSA, dynamics simulations and DFT analysis
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Oxime-dipeptides as anticholinesterase, reactivator of phosphonylated-serine of AChE catalytic triad: probing the mechanistic insight by MM-GBSA, dynamics simulations and DFT analysis

机译：肟二肽作为抗胆碱酯酶，AChE催化三联体的磷酸化丝氨酸的活化剂：通过MM-GBSA，动力学模拟和DFT分析探索机理

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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 pi-pi 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.
机译：神经病理学级联反应导致阿尔茨海默氏病胆碱能传递减少，导致AChE抑制剂的发展。尽管某些抑制剂的致死剂量会导致AChE介导的机制中断，但可逆的AChE抑制剂可帮助保护其免受AChE的抑制作用，因此，为了探究潜在分子作为抗胆碱酯酶和激活剂，已在这项工作中采用了基于计算结构的方法用于设计新的2-氨基-3-吡啶肟基-二肽结合物。我们将MD模拟与灵活的配体对接方法相结合，以确定2-氨基-3-吡啶肟基二肽对AChE（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pi-pi相互作用，与Asp74和Tyr341的侧链的氢键结合（Gscore -10.801和MM-GBSA自由能-34.89 kcal / mol）。对接结果描述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。在具有NPT和NVT集成的显式溶剂系统下，对2-氨基-3-吡啶肟-（Arg-Asn）AChE体系进行了MD模拟。 MD模拟揭示了2-氨基-3-吡啶肟-（Arg-Asn）的动态行为，并揭示了其移动性质和形成与活性位点残基形成强距离接触的能力，以接近抑制的丝氨酸残基并通过氢的大量贡献而促进结合和水桥，以及相邻重要残基的缓慢大幅度移动。为了评估完整的潜在表面轮廓，已通过DFT方法在真空MO6 / 6-311G（d，p）水平上研究了2-氨基-3-吡啶肟诱导的沙林-丝氨酸加合物的再活化途径。 Poisson-Boltzmann溶剂化模型，发现具有较低的能垒。 pKa评估显示pKa为6.47的主要去质子化的2-amino-3-pyridoixime物质，因此使2-氨基-3-pyridoxime-（Arg-Asn）潜在的抗胆碱酯酶和AChE在生理pH下的活化剂成为可能。

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