Laboratory of Radiobiology and Molecular Genetics-080, Institute of Nuclear Sciences Vinca, National Institute of the Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia.
Laboratory for Bioinformatics and Computational Chemistry, Institute of Nuclear Sciences Vinca, National Institute of the Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia.
Molecules. 2022 Apr 19;27(9):2626. doi: 10.3390/molecules27092626.
Alzheimer's disease (AD), a devastating neurodegenerative disease, is the focus of pharmacological research. One of the targets that attract the most attention for the potential therapy of AD is the serotonin 5HT6 receptor, which is the receptor situated exclusively in CNS on glutamatergic and GABAergic neurons. The neurochemical impact of this receptor supports the hypothesis about its role in cognitive, learning, and memory systems, which are of critical importance for AD. Natural products are a promising source of novel bioactive compounds with potential therapeutic potential as a 5HT6 receptor antagonist in the treatment of AD dementia. The ZINC-natural product database was in silico screened in order to find the candidate antagonists of 5-HT6 receptor against AD. A virtual screening protocol that includes both short-and long-range interactions between interacting molecules was employed. First, the EIIP/AQVN filter was applied for in silico screening of the ZINC database followed by 3D QSAR and molecular docking. Ten best candidate compounds were selected from the ZINC Natural Product database as potential 5HT6 Receptor antagonists and were proposed for further evaluation. The best candidate was evaluated by molecular dynamics simulations and free energy calculations.
阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，是药物研究的重点。吸引最多注意力用于 AD 潜在治疗的靶点之一是 5-羟色胺 5HT6 受体，它是唯一位于中枢神经系统的谷氨酸能和 GABA 能神经元上的受体。该受体的神经化学影响支持了其在认知、学习和记忆系统中的作用的假说，这些系统对 AD 至关重要。天然产物是具有潜在治疗潜力的新型生物活性化合物的有希望的来源，可作为治疗 AD 痴呆的 5HT6 受体拮抗剂。对 ZINC 天然产物数据库进行了计算机筛选，以寻找针对 AD 的 5-HT6 受体的候选拮抗剂。采用了一种包括相互作用分子之间短程和远程相互作用的虚拟筛选方案。首先，应用 EIIP/AQVN 过滤器对 ZINC 数据库进行计算机筛选，然后进行 3D-QSAR 和分子对接。从 ZINC 天然产物数据库中选择了十个最佳候选化合物作为潜在的 5HT6 受体拮抗剂，并提出进一步评估。通过分子动力学模拟和自由能计算评估了最佳候选物。
