Abstract
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.
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Data availability
The datasets generated in our current study are available in the following sites. Target prediction: http://www.swisstargetprediction.ch/result.php?job=312048511&organism=Homo_sapiens. GalaxyRefine: http://galaxy.seoklab.org/cgi-bin/report_REFINE.cgi?key=1b5e664952f2910cdae12d4a634b0383. PROCHECK: https://saves.mbi.ucla.edu/results?job=592099&p=procheck. ERRAT: https://saves.mbi.ucla.edu/results?job=592099&p=errat. COACH active site prediction: http://zhanglab.ccmb.med.umich.edu/COACH/output/CH056080.
The datasets generated for homology modeling are not publicly available which was available online for 2 months only. But it can be available from corresponding author on reasonable request.
Abbreviations
- ADK:
-
Adenosine kinase
- CNS:
-
Central nervous system
- BBB:
-
Blood-brain barrier
- AMP:
-
Adenosine monophosphate
- SAH:
-
S-adenosylhomocysteine
- GPCR:
-
G protein coupled receptor
- ADMET:
-
Absorption distribution metabolism excretion toxicity
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Acknowledgements
P SathishKumar thanks UGC, NewDelhi, for providing SRF fellowship under UGC-BSR Meritorious Research Fellowship Scheme (F.No. 25-1/2014-15(BSR)/7-120/2007(BSR) dated 15.10.2015).
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Dr.Kannan conceived and designed the research. SathishKumar and Suganthana Balasubramaniam conducted the experiments and analyzed the data. SathishKumar wrote the manuscript. All authors read and approved the manuscript.
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Paramashivam, S., Balasubramaniam, S. & Dhiraviam, K.N. Computational exploration of vicine – an alkaloid glycoside mediated pathological hallmark of adenosine kinase to promote neurological disorder. Metab Brain Dis 36, 653–667 (2021). https://doi.org/10.1007/s11011-021-00674-y
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DOI: https://doi.org/10.1007/s11011-021-00674-y