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The effect of mutation on neurotoxicity reduction of new chimeric reteplase, a computational study
Pardis Mohammadi Pour1, Karim Mahnam2, Mahsa Taherzadeh3
1Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Background And Purpose:
Excitotoxicity in nerve cells is a type of neurotoxicity in which excessive stimulation of receptors (such as N-methyl-d-aspartate glutamate receptors (NMDAR)) leads to the influx of high-level calcium ions into cells and finally cell damage or death. This complication can occur after taking some of the plasminogen activators like tissue plasminogen activator and reteplase. The interaction of the kringle2 domain in such plasminogen activator with the amino-terminal domain (ATD) of the NR1 subunit of NMDAR finally leads to excitotoxicity. In this study, we assessed the interaction of two new chimeric reteplase, mutated in the kringle2 domain, with ATD and compared the interaction of wild-type reteplase with ATD, computationally.
Experimental Approach:
Homology modeling, protein docking, molecular dynamic simulation, and molecular dynamics trajectory analysis were used for the assessment of this interaction.
Findings/Results:
The results of the free energy analysis between reteplase and ATD (wild reteplase: -2127.516 ± 0.0, M1-chr: -1761.510 ± 0.0, M2-chr: -521.908 ± 0.0) showed lower interaction of this chimeric reteplase with ATD compared to the wild type.
Conclusion And Implications:
The decreased interaction between two chimeric reteplase and ATD of NR1 subunit in NMDAR which leads to lower neurotoxicity related to these drugs, can be the start of a way to conduct more tests and if the results confirm this feature, they can be considered potential drugs in acute ischemic stroke treatment.
Insights
New reteplase variants show reduced interaction with N-methyl-d-aspartate glutamate receptors (NMDAR), potentially lowering neurotoxicity. This finding may lead to safer treatments for acute ischemic stroke.
Area of Science:
- Neuroscience
- Pharmacology
- Computational Biology
Background:
- Excitotoxicity, a form of neurotoxicity, involves excessive N-methyl-d-aspartate glutamate receptor (NMDAR) stimulation leading to cell death.
- Plasminogen activators like reteplase can cause excitotoxicity through interaction with the NMDAR NR1 subunit's amino-terminal domain (ATD).
Purpose of the Study:
- To computationally assess the interaction between wild-type reteplase and NMDAR ATD.
- To evaluate the interaction of two novel chimeric reteplase variants, mutated in the kringle2 domain, with NMDAR ATD.
Main Methods:
- Homology modeling
- Protein docking
- Molecular dynamic simulation
- Molecular dynamics trajectory analysis
Main Results:
- Free energy analysis revealed significantly lower interaction between the chimeric reteplase variants (M1-chr, M2-chr) and NMDAR ATD compared to wild-type reteplase.
- Wild-type reteplase: -2127.516 ± 0.0; M1-chr: -1761.510 ± 0.0; M2-chr: -521.908 ± 0.0.
Conclusions:
- The reduced interaction of chimeric reteplase variants with NMDAR ATD suggests lower associated neurotoxicity.
- These variants could represent potential therapeutic candidates for acute ischemic stroke treatment, warranting further investigation.
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