背景:阿尔茨海默病(AD)是当今已知的最具破坏性和最普遍的神经退行性疾病之一。研究人员已经确定了与AD相关的几种酶靶标,其中糖原合成酶激酶3β(GSK-3β)和乙酰胆碱酯酶(AChE)是突出的靶标。不幸的是,市场提供治疗或管理AD的药物很少,没有一个对它有明显的疗效。
目标:为了解决这一关键问题,双重抑制剂的设计和发现将代表对抗AD的潜在突破。在追求设计新型双重抑制剂的过程中,我们探索了tacrine和金刚烷胺脲连接的酰胺类似物如GSK-3β和AChE双重抑制剂用于减少AD的分子对接和动力学分析。Tacrine和adamantine是FDA批准的药物,经过结构修饰以设计和开发新型候选药物,这些候选药物可能同时表现出对GSK-3β和AChE的双重选择性。
方法:在以下研究中,分子对接是通过使用AutoDockVina执行的,使用Desmond进行了分子动力学和ADMET预测,薛定谔的Qikprop模块。
结果:我们的发现表明,化合物DST2和DST11与GSK-3β和AChE的活性位点表现出显著的分子相互作用,分别。这些化合物与关键氨基酸有效相互作用,即Lys85、Val135、Asp200和Phe295,产生-9.7和-12.7kcal/mol的非常有利的对接能量。此外,通过跨越100ns轨迹的分子动力学模拟,我们证实了配体DST2和DST11在GSK-3β和AChE活性腔内的稳定性。表现出最有希望的对接结果的化合物也表现出优异的ADMET特征。值得注意的是,DST21显示出76.358%的出色人体口服吸收率,超过其他分子的吸收率。
结论:总体而言,我们的计算机研究表明,设计的分子显示出作为新型抗阿尔茨海默病药物的潜力,能够同时抑制GSK-3β和AChE.所以,在未来,双重抑制剂的设计和开发将预示AD治疗药物设计的新纪元。
BACKGROUND: Alzheimer\'s disease (AD) stands out as one of the most devastating and prevalent neurodegenerative disorders known today. Researchers have identified several enzymatic targets associated with AD among which Glycogen synthase kinase-3β (GSK-3β) and Acetylcholinesterase (
AChE) are prominent ones. Unfortunately, the market offers very few drugs for treating or managing AD, and none have shown significant efficacy against it.
OBJECTIVE: To address this critical issue, the design and discovery of dual inhibitors will represent a potential breakthrough in the fight against AD. In the pursuit of designing novel dual inhibitors, we explored molecular docking and dynamics analyses of tacrine and amantadine uredio-linked amide analogs such as GSK-3β and
AChE dual inhibitors for curtailing AD. Tacrine and adamantine are the FDA-approved drugs that were structurally modified to design and develop novel drug candidates that may demonstrate concurrently dual selectivity towards GSK-3β and
AChE.
METHODS: In the following study, molecular docking was executed by employing AutoDock Vina, and molecular dynamics and ADMET predictions were made using Desmond, Qikprop modules of Schrödinger.
RESULTS: Our findings revealed that compounds DST2 and DST11 exhibited remarkable molecular interactions with active sites of GSK-3β and
AChE, respectively. These compounds effectively interacted with key amino acids, namely Lys85, Val135, Asp200, and Phe295, resulting in highly favourable docking energies of -9.7 and -12.7 kcal/mol. Furthermore, through molecular dynamics simulations spanning a trajectory of 100 ns, we confirmed the stability of ligands DST2 and DST11 within the active cavities of GSK-3β and
AChE. The compounds exhibiting the most promising docking results also demonstrated excellent ADMET profiles. Notably, DST21 displayed an outstanding human oral absorption rate of 76.358%, surpassing the absorption rates of other molecules.
CONCLUSIONS: Overall, our in-silico studies revealed that the designed molecules showed potential as novel anti-Alzheimer agents capable of inhibiting both GSK-3β and AChE simultaneously. So, in the future, the designing and development of dual inhibitors will harbinger a new era of drug design in AD treatment.