Alvarado Ysaías J, González-Paz Lenin, Paz José L, Loroño-González Marcos A, Santiago Contreras Julio, Lossada Carla, Vivas Alejandro, Marrero-Ponce Yovani, Martinez-Rios Felix, Rodriguez-Lugo Patricia, Balladores Yanpiero, Vera-Villalobos Joan
Laboratorio de Química Biofísica Experimental y Teórica (LQBET), Instituto Venezolano de Investigaciones Científicas (IVIC), Centro de Biomedicina Molecular (CBM), Maracaibo 4001, Zulia, República Bolivariana de Venezuela.
Laboratorio de Modelado, Dinamica y Bioquímica Subcelular (LMDBS), Instituto Venezolano de Investigaciones Científicas (IVIC), Centro de Biomedicina Molecular (CBM), Maracaibo 4001, Zulia, República Bolivariana de Venezuela.
Biology (Basel). 2024 Dec 19;13(12):1065. doi: 10.3390/biology13121065.
The enzyme acetylcholinesterase (AChE) plays a crucial role in the termination of nerve impulses by hydrolyzing the neurotransmitter acetylcholine (ACh). The inhibition of AChE has emerged as a promising therapeutic approach for the management of neurological disorders such as Lewy body dementia and Alzheimer's disease. The potential of various compounds as AChE inhibitors was investigated. In this study, we evaluated the impact of natural compounds of interest on the intrinsic deformability of human AChE using computational biophysical analysis. Our approach incorporates classical dynamics, elastic networks (ENM and NMA), statistical potentials (CUPSAT and SWOTein), energy frustration (Frustratometer), and volumetric cavity analyses (MOLE and PockDrug). The results revealed that cyanidin induced significant changes in the flexibility and rigidity of AChE, especially in the distribution and volume of internal cavities, compared to model inhibitors such as TZ2PA6, and through a distinct biophysical-molecular mechanism from the other inhibitors considered. These findings suggest that cyanidin could offer potential mechanistic pathways for future research and applications in the development of new treatments for neurodegenerative diseases.
乙酰胆碱酯酶（AChE）通过水解神经递质乙酰胆碱（ACh）在神经冲动的终止过程中发挥关键作用。抑制AChE已成为治疗诸如路易体痴呆和阿尔茨海默病等神经疾病的一种有前景的治疗方法。研究了各种化合物作为AChE抑制剂的潜力。在本研究中，我们使用计算生物物理分析评估了感兴趣的天然化合物对人AChE固有变形性的影响。我们的方法包括经典动力学、弹性网络（弹性网络模型和正常模式分析）、统计势（CUPSAT和SWOTein）、能量挫折（Frustratometer）和体积腔分析（MOLE和PockDrug）。结果显示，与TZ2PA6等模型抑制剂相比，花青素诱导了AChE灵活性和刚性的显著变化，特别是内腔的分布和体积变化，并且通过与所考虑的其他抑制剂不同的生物物理分子机制产生这些变化。这些发现表明，花青素可为未来神经退行性疾病新疗法开发的研究和应用提供潜在的作用机制途径。
