Departamento de Química e Física Molecular, Instituto de Química de São Carlos, Universidade de São Paulo, C.P 780, 13560-970, São Carlos, SP, Brazil.
Escola de Artes, Ciência e Humanidades, Universidade de São Paulo, São Paulo, 03828-000, Brazil.
J Mol Graph Model. 2021 May;104:107844. doi: 10.1016/j.jmgm.2021.107844. Epub 2021 Jan 18.
Alzheimer's Disease (AD) is the most frequent illness and cause of death amongst the age related-neurodegenerative disorders. The Alzheimer's Disease International (ADI) reported in 2019 that over 50 million people were living with dementia in the world and this number could potentially be around 152 million by 2050.5-hydroxtryptamine subtype 6 receptor (5-HTR) has been identified as a potential anti-amnesic drug target and therefore, the administration of 5-HTR antagonists can likely mitigate the memory loss and intellectual deterioration associated with AD. Herein, computational tools were applied to design new 5-HT antagonists and their biological activity values were predicted by our QSAR model obtained from Artificial Neural Networks (ANN). The proposed compounds here from the QSAR-ANN model presented significant biological activity values and some of them have achieved pK above 9.00. Furthermore, our results suggest that the presence of halogen atoms (especially bromine) linked to the aromatic ring at para-position (HYD) contribute considerably to the increase of the biological activity values while bulky groups in the PI position do not culminate with the increase antagonist activity of compounds here analyzed. Finally, the ADME/Tox profile as well as the synthetic accessibility of new proposed compounds qualify them to go on further with experimental procedures and thenceforward their antagonist effects can be confirmed.
阿尔茨海默病（AD）是最常见的疾病，也是与年龄相关的神经退行性疾病的主要死因。2019 年，国际阿尔茨海默病协会（ADI）报告称，全球有超过 5000 万人患有痴呆症，到 2050 年，这一数字可能会达到 1.52 亿。5-羟色胺亚型 6 受体（5-HTR）已被确定为一种潜在的抗遗忘药物靶点，因此，5-HTR 拮抗剂的给药可能有助于减轻与 AD 相关的记忆丧失和智力下降。在此，应用计算工具设计了新的 5-HT 拮抗剂，并通过我们从人工神经网络（ANN）获得的 QSAR 模型预测了它们的生物学活性值。本文中从 QSAR-ANN 模型提出的化合物具有显著的生物学活性值，其中一些化合物的 pK 值超过了 9.00。此外，我们的结果表明，芳香环对位（HYD）上连接卤素原子（尤其是溴）的存在对增加生物学活性值有很大贡献，而 PI 位置上的大基团并不能导致所分析化合物的拮抗剂活性增加。最后，新提出的化合物的 ADME/Tox 概况和合成可及性使它们有资格进行进一步的实验程序，从而可以证实它们的拮抗剂作用。
