Tanoli Nazish U, Tanoli Sheraz A K, Ferreira Antonio G, Mehmood Mazhar, Gul Sana, Monteiro Julia L, Vieira Lucas C C, Venâncio Tiago, Correa Arlene G, Ul-Haq Zaheer
Department of Metallurgy and Materials Engneering, Pakistan Institute of Engineering and Applied Sciences (PIEAS), Lehtrar Road, Nilore, Islamabad, 45650, Pakistan.
Laboratory of Nuclear Magnetic Resonance, Federal University of São Carlos, Rodovia Washington Luiz, Km 235, São Carlos, SP, 13565-905, Brazil.
J Mol Model. 2018 Jul 14;24(8):207. doi: 10.1007/s00894-018-3751-3.
Alzheimer's disease (AD) is one of the most common forms of dementia and a significant threat to the elderly populations, especially in the Western world. The rapid hydrolysis of the principal neurotransmitter into choline and acetate by acetylcholinesterase (AChE) at synapses causes the loss of cognitive response that becomes the real cause of AD. Therefore, inhibition of AChE is the most fundamental therapy among currently available treatments for AD. In this context, we designed and performed molecular recognitions studies of coumarin-based inhibitors towards AChE. STD NMR and Tr-NOESY applications were utilized to evaluate the binding epitope, the dissociation constant (K) and bound conformations of these inhibitors within this inhibitor-AChE complex. Compound 1, which has a similar inhibition activity to tacrine (a current drug) led in this study as a stronger binder with K = 30 μM ,even greater than tacrine (K = 140 μM). Moreover, docking simulations mimic NMR results and provided evidence of synchronizing binding of compound 1 with three sites; the peripheral anionic site, the bottom of the gorge, and the catalytic site. Therefore, we envisioned from our experimental and theoretical results that coumarin-based inhibitors containing a piperidinyl scaffold might be a potential drug candidates for AD in the future.
阿尔茨海默病（AD）是最常见的痴呆形式之一，对老年人群构成重大威胁，尤其是在西方世界。在突触处，主要神经递质被乙酰胆碱酯酶（AChE）快速水解为胆碱和乙酸盐，导致认知反应丧失，这成为AD的真正病因。因此，抑制AChE是目前AD现有治疗方法中最基本的治疗手段。在此背景下，我们设计并开展了基于香豆素的抑制剂对AChE的分子识别研究。利用饱和转移差核磁共振（STD NMR）和转移核Overhauser效应光谱（Tr-NOESY）技术评估这些抑制剂在该抑制剂 - AChE复合物中的结合表位、解离常数（K）和结合构象。化合物1具有与他克林（一种现有药物）相似的抑制活性，在本研究中作为更强的结合剂，K = 30 μM，甚至大于他克林（K = 140 μM）。此外，对接模拟模拟了核磁共振结果，并提供了化合物1与三个位点同步结合的证据；外周阴离子位点、峡谷底部和催化位点。因此，从我们的实验和理论结果可以设想，含有哌啶基支架的基于香豆素的抑制剂未来可能是AD的潜在候选药物。
