Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research-Raebareli (NIPER-R), Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow-226002, U.P., India.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Raebareli (NIPER-R), Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow-226002, U.P., India.
Cent Nerv Syst Agents Med Chem. 2021;21(1):39-52. doi: 10.2174/1871524920666201119144535.
Alzheimer's disease (AD), an irreversible complex neurodegenerative disorder, is the most common type of dementia, with progressive loss of cholinergic neurons. Based on the multi-factorial etiology of Alzheimer's disease, novel ligands strategy appears as an up-coming approach for the development of newer molecules against AD. This study is envisaged to investigate anti-Alzheimer's potential of 10 synthesized compounds. The screening of compounds (1-10) was carried out using in silico techniques.
For in silico screening of physicochemical properties of compounds, Molinspiration property engine v.2018.03, Swiss ADME online web-server and pkCSM ADME were used. For pharmacodynamic prediction, PASS software was used, while the toxicity profile of compounds was analyzed through ProTox-II online software. Simultaneously, molecular docking analysis was performed on mouse AChE enzyme (PDB ID:2JGE, obtained from RSCB PDB) using Auto Dock Tools 1.5.6.
Based on in silico studies, compound 9 and 10 have been found to have better druglikeness, LD50 value, better anti-Alzheimer's, and nootropic activities. However, these compounds had poor blood-brain barrier (BBB) permeability. Compounds 4 and 9 were predicted with a better docking score for the AChE enzyme.
The outcome of in silico studies has suggested, out of various substitutions at different positions of pyridoxine-carbamate, compound 9 has shown promising drug-likeness, with better safety and efficacy profile for anti-Alzheimer's activity. However, BBB permeability appears as one of the major limitations of all these compounds. Further studies are required to confirm its biological activities.
阿尔茨海默病（AD）是一种不可逆的复杂神经退行性疾病，是最常见的痴呆类型，其胆碱能神经元逐渐丧失。基于阿尔茨海默病的多因素病因，新型配体策略似乎是开发新型抗 AD 分子的一种有前途的方法。本研究旨在研究 10 种合成化合物的抗阿尔茨海默病潜力。使用计算机技术对化合物（1-10）进行了筛选。
为了对化合物的理化性质进行计算机筛选，使用了 Molinspiration 属性引擎 v.2018.03、瑞士 ADME 在线网络服务器和 pkCSM ADME。为了进行药效预测，使用了 PASS 软件，同时通过 ProTox-II 在线软件分析了化合物的毒性概况。同时，使用 Auto Dock Tools 1.5.6 对来自 RSCB PDB 的鼠标乙酰胆碱酯酶（PDB ID：2JGE）进行了分子对接分析。
根据计算机研究，发现化合物 9 和 10 具有更好的类药性、LD50 值、更好的抗阿尔茨海默病和促智活性。然而，这些化合物的血脑屏障（BBB）通透性较差。化合物 4 和 9 被预测对乙酰胆碱酯酶具有更好的对接评分。
计算机研究的结果表明，在不同位置对吡啶酮-氨基甲酸酯进行各种取代后，化合物 9 显示出有前途的类药性，具有更好的安全性和抗阿尔茨海默病功效。然而，BBB 通透性似乎是所有这些化合物的主要限制之一。需要进一步的研究来确认其生物学活性。
