Department of Plant Biotechnology, School of Biotechnology, Madurai Kamaraj University, Madurai, Tamilnadu, 625021, India.
Department of Chemistry, Fatima College, Madurai, Tamilnadu, 625001, India.
Metab Brain Dis. 2021 Apr;36(4):653-667. doi: 10.1007/s11011-021-00674-y. Epub 2021 Jan 26.
Epilepsy disease is characterized by the neuronal dysfunction or abnormal neuronal activity of the brain which is regulated by astrocytes. These are glial cells and found to be the major regulators of the brain which are guided by the occurrence of adenosine kinase (ADK) enzyme in the central nervous system (CNS). During the normal physiological environment, ADK maintains the level of adenosine in the CNS. Dysfunction of ADK levels results in accumulation of adenosine levels in the CNS that leads to the pathophysiology of the brain such as astrogliosis which is a pathological hallmark of epileptic seizures. Vicine, an alkaloid glycoside in bitter gourd juice (Momordica charantia) is found to be toxic to the human system if the bitter gourd juice is consumed more. This compound inhibits ADK enzyme activity to lead epilepsy and seizure. Here, the toxic effect of vicine targeting ADK using computational predictions was investigated. The 3-dimensional structure of ADK has been constructed using I-Tasser, which has been refined by ModRefiner, GalaxyRefine, and 3D refine and it was endorsed using PROCHECK, ERRAT, and VADAR. 3D structure of the ligand molecule has been obtained from PubChem. Molecular docking has been achieved using AutoDock 4.2 software, from which the outcome showed the effective interaction between vicine and ADK, which attains binding free energy (∆G) of - 4.13 kcal/mol. Vicine molecule interacts with the active region ARG 149 of ADK and inhibits the functions of ADK that may cause imbalance in energy homeostasis. Also, pre-ADMET results robustly propose in which vicine possesses toxicity, and meanwhile, from the Ames test, it was shown as mutagenic. Hence, the results from our study suggest that vicine was shown to be toxic that suppresses the ADK activity to undergo pathological conditions in the neuronal junctions to lead epilepsy.
癫痫疾病的特征是大脑神经元功能障碍或异常神经元活动，而大脑神经元活动由星形胶质细胞调节。星形胶质细胞是神经胶质细胞，被认为是大脑的主要调节者，其受中央神经系统（CNS）中腺苷激酶（ADK）酶的控制。在正常生理环境中，ADK 维持 CNS 中的腺苷水平。ADK 水平的功能障碍导致 CNS 中腺苷水平的积累，从而导致大脑的病理生理学，如星形胶质细胞增生，这是癫痫发作的病理标志。苦瓜汁（Momordica charantia）中的生物碱糖苷葫芦巴碱，如果苦瓜汁摄入过多，会对人体系统造成毒性。该化合物抑制 ADK 酶的活性，导致癫痫和惊厥。在这里，使用计算预测研究了葫芦巴碱针对 ADK 的毒性作用。使用 I-Tasser 构建了 ADK 的 3 维结构，使用 ModRefiner、GalaxyRefine 和 3D refine 对其进行了细化，并使用 PROCHECK、ERRAT 和 VADAR 对其进行了验证。配体分子的 3 维结构从 PubChem 获得。使用 AutoDock 4.2 软件进行分子对接，结果表明葫芦巴碱与 ADK 之间存在有效相互作用，达到结合自由能（∆G）为-4.13 kcal/mol。葫芦巴碱分子与 ADK 的活性区域 ARG 149 相互作用，并抑制 ADK 的功能，可能导致能量平衡失调。此外，预 ADMET 结果稳健地表明，葫芦巴碱具有毒性，同时，从艾姆斯试验来看，它具有致突变性。因此，我们的研究结果表明，葫芦巴碱具有毒性，它抑制 ADK 活性，导致神经元连接处发生病理状况，从而引发癫痫。
