Londhe Saurabh G, Walhekar Vinayak, Shenoy Mangala, Kini Suvarna G, Scotti Marcus T, Scotti Luciana, Kumar Dileep
Department of Pharmaceutical Chemistry, BVDU's Poona College of Pharmacy, Pune 411038, India.
Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India.
Pharmaceutics. 2024 Jul 26;16(8):991. doi: 10.3390/pharmaceutics16080991.
Alzheimer's disease is a serious and widespread neurodegenerative illness in the modern healthcare scenario. GSK-3β and BuChE are prominent enzymatic targets associated with Alzheimer's disease. Co-targeting GSK3β and BChE in Alzheimer's disease helps to modify disease progression and enhance cognitive function by addressing both tau pathology and cholinergic deficits. However, the treatment arsenal for Alzheimer's disease is extremely inadequate, with present medications displaying dismal success in treating this never-ending ailment. To create novel dual inhibitors, we have used molecular docking and dynamics analysis. Our focus was on analogs formed from the fusion of tacrine and amantadine ureido, specifically tailored to target GSK-3β and BuChE.
In the following study, molecular docking was executed by employing AutoDock Vina and molecular dynamics and ADMET predictions were performed using the Desmond and Qikprop modules of Schrödinger.
Our findings unveiled that compounds DKS1 and DKS4 exhibited extraordinary molecular interactions within the active domains of GSK-3β and BuChE, respectively. These compounds engaged in highly favorable interactions with critical amino acids, including Lys85, Val135, Asp133, and Asp200, and His438, Ser198, and Thr120, yielding encouraging docking energies of -9.6 and -12.3 kcal/mol. Additionally, through extensive molecular dynamics simulations spanning a 100 ns trajectory, we established the robust stability of ligands DKS1 and DKS4 within the active pockets of GSK-3β and AChE. Particularly noteworthy was DKS5, which exhibited an outstanding human oral absorption rate of 79.792%, transcending the absorption rates observed for other molecules in our study.
In summary, our in silico findings have illuminated the potential of our meticulously designed molecules as groundbreaking agents in the fight against Alzheimer's disease, capable of simultaneously inhibiting both GSK-3β and BuChE.
在现代医疗环境中，阿尔茨海默病是一种严重且广泛流行的神经退行性疾病。糖原合成酶激酶-3β（GSK-3β）和丁酰胆碱酯酶（BuChE）是与阿尔茨海默病相关的重要酶靶点。在阿尔茨海默病中共同靶向GSK3β和BChE有助于通过解决tau病理和胆碱能缺陷来改变疾病进程并增强认知功能。然而，阿尔茨海默病的治疗手段极其不足，目前的药物在治疗这种难治之症方面成效甚微。为了创制新型双抑制剂，我们采用了分子对接和动力学分析。我们的重点是由他克林和金刚烷脲融合形成的类似物，专门针对GSK-3β和BuChE进行设计。
在以下研究中，使用AutoDock Vina进行分子对接，并使用薛定谔的Desmond和Qikprop模块进行分子动力学和ADMET预测。
我们的研究结果表明，化合物DKS1和DKS4分别在GSK-3β和BuChE的活性域内表现出非凡的分子相互作用。这些化合物与关键氨基酸，包括Lys85、Val135、Asp133和Asp200，以及His438、Ser198和Thr120，进行了高度有利的相互作用，产生了令人鼓舞的对接能量-9.6和-12.3千卡/摩尔。此外，通过跨越100纳秒轨迹的广泛分子动力学模拟，我们确定了配体DKS1和DKS4在GSK-3β和乙酰胆碱酯酶（AChE）活性口袋内的强大稳定性。特别值得注意的是DKS5，其表现出79.792%的出色人体口服吸收率，超过了我们研究中观察到的其他分子的吸收率。
总之，我们的计算机模拟研究结果揭示了我们精心设计的分子作为抗击阿尔茨海默病的开创性药物的潜力，能够同时抑制GSK-3β和BuChE。
