Alam Perwez, Arshad Mohammed Faiz, Sharma Pradeep
Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O Box 2457, Riyadh, 11451, Saudi Arabia.
Department of Research and Scientific Communications, Isthmus Research and Publishing House, New Delhi, 110044, India.
Mol Neurobiol. 2025 Apr 22. doi: 10.1007/s12035-025-04935-0.
Neurological disorders, including Down syndrome, Alzheimer's disease, and autism spectrum disorders, involve intricate disruptions in brain function and development. DYRK1A (Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A) has become an essential target in these diseases because it helps neurons grow, differentiate, and change shape. Overexpression of DYRK1A is connected to problems with neurodevelopment, memory loss, and tauopathies, which makes it an essential target for therapy. Therefore, inhibiting the DYRK1A protein aids in maintaining the normal brain molecular mechanism. Herein, we have identified three major natural compounds, ZINC000043552589, ZINC000001562130, and ZINC000059779788, as potential inhibitory candidates. These compounds exhibited a strong binding affinity with the DYRK1A protein during virtual screening and molecular docking. During the virtual screening analysis, the binding scores of these compounds were more than -11.0 kcal/mol. Further, hydrogen and hydrophobic interactions strengthen their binding with the DYRK1A protein. The MD simulation analysis also confirmed the structural dynamic stability of the compounds. Moreover, the total free binding energy calculated via the MM/GBSA method was found to be -54.06 kcal/mol for ZINC000043552589, -39.01 kcal/mol for ZINC000001562130 and -50.26 kcal/mol for ZINC000059779788. These values further confirm the binding affinity strength of the compounds with the target protein. DFT analysis revealed distinct HOMO-LUMO energy gaps and orbital distributions across the compounds, highlighting their varied electronic characteristics and charge-transfer potentials. Network pharmacology analysis further highlighted multiple potential gene targets for the selected compounds, providing insights into their broader therapeutic implications. This analysis suggests these natural compounds may modulate additional pathways relevant to neurodevelopmental and neurodegenerative diseases.
包括唐氏综合征、阿尔茨海默病和自闭症谱系障碍在内的神经疾病，涉及大脑功能和发育的复杂紊乱。双特异性酪氨酸磷酸化调节激酶1A（DYRK1A）已成为这些疾病的一个重要靶点，因为它有助于神经元生长、分化和改变形状。DYRK1A的过表达与神经发育问题、记忆丧失和tau蛋白病有关，这使其成为治疗的重要靶点。因此，抑制DYRK1A蛋白有助于维持正常的大脑分子机制。在此，我们已鉴定出三种主要的天然化合物，即ZINC000043552589、ZINC000001562130和ZINC000059779788，作为潜在的抑制候选物。在虚拟筛选和分子对接过程中，这些化合物与DYRK1A蛋白表现出很强的结合亲和力。在虚拟筛选分析中，这些化合物的结合分数超过-11.0千卡/摩尔。此外，氢键和疏水相互作用增强了它们与DYRK1A蛋白的结合。分子动力学模拟分析也证实了这些化合物的结构动态稳定性。此外，通过MM/GBSA方法计算得出，ZINC000043552589的总自由结合能为-54.06千卡/摩尔，ZINC000001562130为-39.01千卡/摩尔，ZINC000059779788为-50.26千卡/摩尔。这些值进一步证实了这些化合物与靶蛋白的结合亲和力强度。密度泛函理论分析揭示了这些化合物不同的最高占据分子轨道-最低未占据分子轨道（HOMO-LUMO）能隙和轨道分布，突出了它们不同的电子特性和电荷转移潜力。网络药理学分析进一步突出了所选化合物的多个潜在基因靶点，为它们更广泛的治疗意义提供了见解。该分析表明，这些天然化合物可能会调节与神经发育和神经退行性疾病相关的其他途径。
