Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University, Sofia, Bulgaria.
Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University, Sofia, Bulgaria.
J Mol Graph Model. 2023 Jul;122:108471. doi: 10.1016/j.jmgm.2023.108471. Epub 2023 Apr 14.
An in silico consensus molecular docking approach and in vitro evaluations were adopted in the present study to explore a dataset of FDA-approved drugs as novel multitarget MAO-B/AChE agents in the treatment of Alzheimer's disease (AD). GOLD 5.3 and Glide were employed in the virtual assessments and consensus superimpositions of the obtained poses were applied to increase the reliability of the docking protocols. Furthermore, the top ranked molecules were subjected to binding free energy calculations using MM/GBSA, Induced fit docking (IFD) simulations, and a literature review. Consequently, the top four multitarget drugs were examined for their in vitro MAO-B and AChE inhibition effects. The consensus molecular docking identified Dolutegravir, Rebamipide, Loracarbef and Diflunisal as potential multitarget drugs. The biological data demonstrated that most of the docking scores were in good correlation with the in vitro experiments, however the theoretical simulations in the active site of MAO-B identified two false-positives - Rebamipide and Diflunisal. Dolutegravir and Loracarbef were accessed as active MAO-B inhibitors, while Dolutegravir, Rebamapide and Diflunisal as potential AChE inhibitors. The antiretroviral agent Dolutegravir exhibited the most potent multitarget activity - 41% inhibition of MAO-B (1 μM) and 68% inhibition of AChE (10 μM). Visualizations of the intermolecular interactions of Dolutegravir in the active sites of MAO-B and AChE revealed the formation of several stable hydrogen bonds. Overall, Dolutegravir was identified as a potential anti-AD drug, however further in vivo evaluations should be considered.
本研究采用计算机共识分子对接方法和体外评价，探索了一组已获美国食品药品监督管理局批准的药物，以寻找新的多靶点 MAO-B/AChE 抑制剂，用于治疗阿尔茨海默病 (AD)。在虚拟评估中使用了 GOLD 5.3 和 Glide，并对获得的构象进行共识叠加，以提高对接方案的可靠性。此外，对排名靠前的分子进行了结合自由能计算，使用 MM/GBSA、诱导契合对接 (IFD) 模拟和文献综述。随后，对前四种多靶点药物进行了体外 MAO-B 和 AChE 抑制作用的检测。共识分子对接鉴定出多替拉韦、瑞巴派特、洛拉卡贝和双氯芬酸作为潜在的多靶点药物。生物学数据表明，大多数对接评分与体外实验相关性良好，但 MAO-B 活性位点的理论模拟鉴定出了两个假阳性——瑞巴派特和双氯芬酸。多替拉韦和洛拉卡贝被认为是有效的 MAO-B 抑制剂，而多替拉韦、瑞巴派特和双氯芬酸被认为是潜在的 AChE 抑制剂。抗逆转录病毒药物多替拉韦表现出最强的多靶点活性——对 MAO-B 的 41%抑制作用（1μM）和对 AChE 的 68%抑制作用（10μM）。多替拉韦在 MAO-B 和 AChE 活性位点的分子间相互作用的可视化显示形成了几个稳定的氢键。总体而言，多替拉韦被鉴定为一种有潜力的抗 AD 药物，但应考虑进一步的体内评估。
