Laboratory of Innovative Technologies, National School of Applied Sciences of Tangier, Abdelmalek Essaadi University, Tetouan, Morocco.
School of Biotechnology, Gautam Buddha University, Greater Noida, India.
J Biomol Struct Dyn. 2024;42(20):11167-11184. doi: 10.1080/07391102.2023.2260879. Epub 2023 Sep 27.
Parkinson's disease is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the midbrain. Current treatments provide limited symptomatic relief without halting disease progression. A multi-targeting approach has shown potential benefits in treating neurodegenerative diseases. In this study, we employed approaches to explore the COCONUT natural products database and identify novel drug candidates with multi-target potential against relevant Parkinson's disease targets. QSAR models were developed to screen for potential bioactive molecules, followed by a hybrid virtual screening approach involving pharmacophore modeling and molecular docking against MAO-B, AAR, and NMDAR. ADME evaluation was performed to assess drug-like properties. Our findings revealed 22 candidates that exhibited the desired pharmacophoric features. Particularly, two compounds: CNP0121426 and CNP0242698 exhibited remarkable binding affinities, with energies lower than -10 kcal/mol and promising interaction profiles with the chosen targets. Furthermore, all the ligands displayed desirable pharmacokinetic properties for brain-targeted drugs. Lastly, molecular dynamics simulations were conducted on the lead candidates, belonging to the dihydrochalcone and curcuminoid class, to evaluate their stability over a 100 ns timeframe and compare their dynamics with reference complexes. Our findings revealed the curcuminoid CNP0242698 to have an overall better stability with the three targets compared to the dihydrochalcone, despite the high ligand RMSD, the curcuminoid CNP0242698 showed better protein stability, implying ligand exploration of different orientations. Similarly, AAR exhibited higher stability with CNP0242698 compared to the reference complex, despite the high initial ligand RMSD due to the bulkier active site. In NMDAR, CNP0242698 displayed good stability and less fluctuations implying a more restricted conformation within the smaller active site of NMDAR. These results may serve as lead compounds for the development and optimization of natural products as multi-target disease-modifying natural remedies for Parkinson's disease patients. However, experimental assays remain necessary to validate these findings.Communicated by Ramaswamy H. Sarma.
帕金森病是一种神经退行性疾病，其特征是中脑中多巴胺能神经元的进行性丧失。目前的治疗方法只能提供有限的症状缓解，而不能阻止疾病的进展。多靶点方法已显示出在治疗神经退行性疾病方面的潜在益处。在这项研究中，我们采用了多种方法来探索 COCONUT 天然产物数据库，并确定具有针对相关帕金森病靶点的多靶点潜力的新型药物候选物。我们开发了 QSAR 模型来筛选潜在的生物活性分子，然后采用混合虚拟筛选方法，包括与 MAO-B、AAR 和 NMDAR 的药效团建模和分子对接。进行了 ADME 评估以评估药物样性质。我们的研究结果揭示了 22 种候选物，它们表现出所需的药效团特征。特别是两种化合物：CNP0121426 和 CNP0242698 表现出显著的结合亲和力，其能量低于-10 kcal/mol，并且与所选靶标具有有前途的相互作用特征。此外，所有配体都表现出针对脑靶向药物的理想药代动力学特性。最后，对属于二氢查耳酮和姜黄素类的先导候选物进行了分子动力学模拟，以评估它们在 100 ns 时间范围内的稳定性，并将它们的动力学与参考复合物进行比较。我们的研究结果表明，与二氢查耳酮相比，姜黄素 CNP0242698 与三个靶标具有更好的整体稳定性，尽管配体 RMSD 较高，但 CNP0242698 表现出更好的蛋白质稳定性，这意味着可以探索不同取向的配体。同样，与参考复合物相比，AAR 与 CNP0242698 表现出更高的稳定性，尽管由于活性位点较大，初始配体 RMSD 较高。在 NMDAR 中，CNP0242698 表现出良好的稳定性和较小的波动，这意味着在 NMDAR 较小的活性位点内具有更受限的构象。这些结果可以作为开发和优化天然产物的先导化合物，作为帕金森病患者的多靶点疾病修饰天然疗法。然而，仍然需要进行实验测定来验证这些发现。由 Ramaswamy H. Sarma 传达。
