Irsal Riyan A Putera, Gholam Gusnia Meilin, Dwicesaria Maheswari Alfira, Mansyah Tiyara F, Chairunisa Fernanda
Departement of Curriculum and Research, Biomatics, Bogor, West Java, Indonesia.
Department of Biochemistry, Faculty of Mathematics and Natural Sciences, Bogor Agricultural University, Bogor, Indonesia.
J Taibah Univ Med Sci. 2024 Dec 12;19(6):1165-1180. doi: 10.1016/j.jtumed.2024.12.005. eCollection 2024 Dec.
Dementia, a growing concern globally, affects more than 55 million people-a number projected to rise to 152 million by 2050. Current medications target Alzheimer's disease, the most prevalent form of dementia. This study investigated L., a plant used in traditional Chinese medicine, as a potential inhibitor of palmitoyl-protein thioesterase 1 (PPT1), an enzyme associated with dementia.
phytochemicals were subjected to docking against PPT1 (PDB ID: 1EH5). Docking simulations were performed in YASARA Structure with VINA scoring. Top-ranked ligands were subjected to ADMET analysis (admetlab 2.0, Protox 3.0) and PASS bioactivity prediction. Stability and reactivity were analyzed with DFT calculations (Gaussian 09), and 500 ns MD simulations (YASARA Structure, AMBER 14 force field) to assess protein-ligand complex stability. MM-PBSA was used to calculate binding free energies.
The docking simulations identified amentoflavone (-9.6 kcal/mol) as the top hit, followed by ferruginol and quercetin 3--pentoside. Amentoflavone formed the most interactions (19) with PPT1. toxicity analysis predicted amentoflavone and quercetin 3--pentoside to be safe, whereas ferruginol violated the Pfizer rule. The PASS server indicated a higher probability of activity for quercetin 3--pentoside (0.423) than amentoflavone (0.287) for dementia treatment. DFT calculations revealed similar electronic properties for both ligands, although amentoflavone showed slightly more favorable values. MD simulations demonstrated that amentoflavone, compared with to galantamine, had superior binding stability in the PPT1 binding pocket.
This study was aimed at identifying potential inhibitors of PPT1 from phytochemicals, given that PPT1 is a target for developing new dementia medications. Our findings identified amentoflavone as a promising candidate for further investigation. These findings warrant further research to validate this compound's potential as a PPT1 inhibitor for dementia treatment.
痴呆症在全球范围内日益受到关注，影响着超过5500万人，预计到2050年这一数字将增至1.52亿。目前的药物主要针对阿尔茨海默病，这是最常见的痴呆症形式。本研究调查了一种传统中药中使用的植物——[植物名称未给出]，作为棕榈酰蛋白硫酯酶1（PPT1）的潜在抑制剂，该酶与痴呆症相关。
对植物化学物质进行与PPT1（蛋白质数据银行ID：1EH5）的对接。在YASARA Structure中使用VINA评分进行对接模拟。对排名靠前的配体进行ADMET分析（admetlab 2.0，Protox 3.0）和PASS生物活性预测。用密度泛函理论计算（高斯09）以及500纳秒的分子动力学模拟（YASARA Structure，AMBER 14力场）分析稳定性和反应性，以评估蛋白质-配体复合物的稳定性。使用MM-PBSA计算结合自由能。
对接模拟确定穗花杉双黄酮（-9.6千卡/摩尔）为最佳命中物，其次是铁杉醇和槲皮素3 - [此处化学结构未完整给出] - 戊糖苷。穗花杉双黄酮与PPT1形成的相互作用最多（19个）。毒性分析预测穗花杉双黄酮和槲皮素3 - [此处化学结构未完整给出] - 戊糖苷是安全的，而铁杉醇违反了辉瑞规则。PASS服务器表明，对于痴呆症治疗，槲皮素3 - [此处化学结构未完整给出] - 戊糖苷（0.423）比穗花杉双黄酮（0.287）具有更高的活性概率。密度泛函理论计算显示两种配体具有相似的电子性质，尽管穗花杉双黄酮的值略更有利。分子动力学模拟表明，与加兰他敏相比，穗花杉双黄酮在PPT1结合口袋中具有更好的结合稳定性。
鉴于PPT1是开发新型痴呆症药物的靶点，本研究旨在从植物化学物质中鉴定PPT1的潜在抑制剂。我们的研究结果确定穗花杉双黄酮是进一步研究的有希望的候选物。这些发现值得进一步研究以验证该化合物作为痴呆症治疗的PPT1抑制剂的潜力。
