John Marshal Jayaraj, Kuriakose Beena Briget, Alhazmi Amani Hamed, Muthusamy Karthikeyan
Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, India.
Department of Basic Medical Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
J Cell Biochem. 2023 Mar;124(3):434-445. doi: 10.1002/jcb.30379. Epub 2023 Feb 13.
Parkinson's disease (PD) is the second most common neurodegenerative disorder that affects dopaminergic neurons in the midbrain. A recent study suggests that Orphan Nuclear Receptor 1 (NURR1) impairment may contribute to PD pathogenesis. Our study found three potent agonists for NURR1 protein based on structural and ligand-based screening methods. The pharmacophore is comprised of a hydrogen bond donor, a hydrophobic group, and two aromatic rings (DHRR). The Pharmacophore screening method screened 3142 compounds, of which 3 were screened using structure-based screening. An analysis of the molecules using Molecular Mechanics-Generalized Born Surface Area (binding free energy) revealed a range of -46.77 to -59.06 Kcal/mol. After that, chemical reactivity was investigated by density functional theory, and molecular dynamics simulation was performed (protein-ligand stability). Based on the computational studies, Lifechemical_16901310, Maybridge_2815310, and NPACT_392450 are promising agonists with respect to NURR1. To confirm the potency of the identified compounds, further validation and experiments must be conducted.
帕金森病（PD）是第二常见的神经退行性疾病，会影响中脑的多巴胺能神经元。最近的一项研究表明，孤儿核受体1（NURR1）功能受损可能与PD的发病机制有关。我们的研究基于结构和配体筛选方法，发现了三种针对NURR1蛋白的强效激动剂。药效团由一个氢键供体、一个疏水基团和两个芳香环（DHRR）组成。药效团筛选方法筛选了3142种化合物，其中3种通过基于结构的筛选进行筛选。使用分子力学-广义玻恩表面积（结合自由能）对分子进行分析，结果显示范围为-46.77至-59.06千卡/摩尔。之后，通过密度泛函理论研究化学反应性，并进行分子动力学模拟（蛋白质-配体稳定性）。基于计算研究，Lifechemical_16901310、Maybridge_2815310和NPACT_392450是关于NURR1的有前景的激动剂。为了确认所鉴定化合物的效力，必须进行进一步的验证和实验。
