针对帕金森病的治疗性 MAO-B 抑制剂的硅内筛选和 ADMET 评估

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摘要

MAO 是一种黄酮酶,有助于多巴胺、血清素和肾上腺素等神经递质的氧化脱氨。MAO 抑制剂是一种抗抑郁药,通过抑制大脑中神经递质的分解来控制情绪。研究表明,具有氯苯-色酮-甲酰胺结构的 MAO 抑制剂非常有效。目前的研究采用了室内筛选、MD 模拟和药物动力学评估等方法,所有这些方法都采用不同的标准进行评估。研究包括 37 种配体,其中有三种配体脱颖而出,其结合得分高于阈值。对接分析发现,化合物 34 的对接得分在该系列中最高(-13.60 kcal/mol),并与 MAO 抑制活性所需的重要氨基酸 TYR 435、CYS 397、CYS 172、PHE 343、TYR 398 和 LYS 296 相互作用。ADMET 研究表明,这些化合物具有类似药物的性质。这项研究的结果可用于开发针对 MAO 抑制剂的色酮类药物。然后使用分子动力学模拟了力和功最大的前三种配体。数据显示,蛋白质配体复合物在整个 100 ns 模拟过程中轨迹稳定。此外,根据 ADMET 分析结果预测的药物相似性表明,前三名先导化合物具有很强的抑制效率、出色的药代动力学,并且在生理环境下无毒。因此,这些化合物有望成为治疗帕金森病的药物。
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In-silico screening and ADMET evaluation of therapeutic MAO-B inhibitors against Parkinson disease

MAOs are flavoenzymes that aid in the oxidative deamination of neurotransmitters such as dopamine, serotonin, and epinephrine. MAO inhibitors are antidepressants that act by inhibiting neurotransmitter breakdown in the brain and controlling mood. MAO inhibitors with the chlorophenyl-chromone-carboxamide structure have been shown in investigations to be extremely effective. The current study employs in-silico screening, MD simulation, and drug kinetics evaluation, all of which are evaluated using different criteria. The study comprised 37 ligands, and three stood out as the best, with greater binding scores above the threshold value. Docking analysis found that compound 34 had the highest docking score in the series (−13.60 ​kcal/mol) and interacted with the important amino acids TYR 435, CYS 397, CYS 172, PHE 343, TYR 398, and LYS 296 required for MAO inhibitory activity. The ADMET study revealed that the compounds had drug-like properties. The results of this study could be used to develop chromone drugs that target the MAO inhibitor. The top three ligands with the highest force and work were then simulated using molecular dynamics. The protein-ligand complexes had steady trajectories throughout the 100 ns simulation, according to the data. Furthermore, the drug likeliness predicted by ADMET analysis findings indicated that the top three lead compounds had strong inhibitory efficiency, superior pharmacokinetics, and were non-toxic under physiological settings. As a result, these compounds have the potential to be exploited as possible treatment medications for PD.

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