Ajala Abduljelil, Asipita Otaru Habiba, Michael Abatyough Terungwa, Tajudeen Murtala Taiwo, Abdulganiyyu Ibrahim A, Ramu Ramith
Department of Chemistry, Faculty of Physical Sciences, Ahmad Bello University, Zaria, Nigeria.
Department of Chemistry, Faculty of Physical Science, Nigerian Defence Academy Kaduna, Kaduna, Nigeria.
In Silico Pharmacol. 2025 Jan 25;13(1):17. doi: 10.1007/s40203-025-00305-9. eCollection 2025.
Parkinson's Disease (PD) is a neurodegenerative disorder that primarily affects persons aged 65 and older. It leads to a decline in motor function as a result of the buildup of abnormal protein deposits called Lewy bodies in the brain. Existing therapies exhibit restricted effectiveness and undesirable side effects. The objective was to discover potent medications that have demonstrated effectiveness in treating PD by employing computational methods. This work employed a comprehensive approach to evaluate 70 pyrimidine derivatives for their potential in treating PD. The evaluation involved the use of QSAR modelling, virtual screening, molecular docking, MD simulation, ADMET analysis, and antagonist inhibitor creation. Six compounds passed all the evaluation, while for MD simulation, carried out between the compound with best docking score and the reference drug, compound 57 was discovered to possess more stability compared to theophylline which is the reference drug, and it functions as a primary inhibitor of the adenosine A receptor. Additionally, the study determined that compound 57 satisfied the Rule of Five (Ro5) standards and exhibited robust physicochemical characteristics. The compound exhibited moderate to low levels of hERG inhibition. The conducted investigations highlighted promising outcomes of natural compounds that can orient towards the rational development of effective Parkinson's disease inhibitors.
The online version contains supplementary material available at 10.1007/s40203-025-00305-9.
帕金森病（PD）是一种主要影响65岁及以上人群的神经退行性疾病。由于大脑中称为路易小体的异常蛋白质沉积物的积累，它导致运动功能下降。现有疗法效果有限且存在不良副作用。目的是通过计算方法发现已证明对治疗帕金森病有效的强效药物。这项工作采用综合方法评估70种嘧啶衍生物治疗帕金森病的潜力。评估包括使用定量构效关系（QSAR）建模、虚拟筛选、分子对接、分子动力学（MD）模拟、药物代谢动力学/药物毒性（ADMET）分析和拮抗剂抑制剂创建。六种化合物通过了所有评估，而在具有最佳对接分数的化合物与参考药物之间进行的分子动力学模拟中，发现化合物57与作为参考药物的茶碱相比具有更高的稳定性，并且它作为腺苷A受体的主要抑制剂发挥作用。此外，该研究确定化合物57符合五规则（Ro5）标准并表现出稳健的物理化学特性。该化合物表现出中度至低度的人乙醚相关基因（hERG）抑制作用。所进行的研究突出了天然化合物的有前景的结果，这些结果可以为有效帕金森病抑制剂的合理开发提供方向。
在线版本包含可在10.1007/s40203-025-00305-9获取的补充材料。
