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Updated: Oct 26, 2025
Induction of Ischemic Stroke and Ischemia-reperfusion in Mice Using the Middle Artery Occlusion Technique and Visualization of Infarct Area
Published on: February 2, 2017
Computational research of mTORC1 inhibitor on cerebral ischemia-reperfusion injury
Hui Li1, Wenzhuo Yang2, Zhenhua Wang2
1Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.
Insights
This study identifies potential mTORC1 inhibitors to combat cerebral ischemia/reperfusion injury after ischemic stroke. Computer-aided drug design and molecular simulations identified promising compounds for neuroprotection.
Area of Science:
- Neuroscience
- Pharmacology
- Computational Chemistry
Background:
- Ischemic stroke is a leading cause of disability and mortality, with cerebral ischemia/reperfusion injury (CIRI) causing secondary nerve damage.
- Autophagy plays a role in CIRI, and the mammalian target of Rapamycin (mTORC1) pathway regulates autophagy.
- mTORC1 inhibitors, like Rapamycin, show neuroprotective effects against CIRI.
Purpose of the Study:
- To screen and design novel mTORC1 inhibitors for controlling reperfusion injury and reducing neuronal death.
- To identify candidate drugs with potential pharmacological properties for treating CIRI.
Main Methods:
- Virtual screening of potential mTORC1 inhibitors using computer-assisted methods (Libdock).
- Toxicity and ADME predictions for small molecules.
- Molecular docking, pharmacophore modeling (Schrodinger), and molecular dynamics simulations to assess binding affinity and complex stability.
- Experimental verification of inhibitory effects of selected compounds (compound 1 and compound 2) on mTOR protein.
Main Results:
- Identification of candidate drugs with potential pharmacological properties.
- Assessment of binding mechanisms and stability of ligand-receptor complexes.
- Experimental validation of inhibitory effects of specific compounds on mTOR protein.
Conclusions:
- The study provides candidate mTORC1 inhibitors for managing cerebral ischemia/reperfusion injury.
- The identified compounds and their properties are crucial for developing new therapeutic strategies against CIRI.
- This research contributes to the development of neuroprotective agents for ischemic stroke patients.
Abstract:
Ischemic stroke contributes to more than 80% of all strokes and has the four characteristics of high prevalence, high disability, high mortality, and high recurrence. Stroke is a preventable and controllable disease. In addition to controlling the primary disease, effective prevention and control measures need to be given to the occurrence and development of stroke. With the development and progress of modern treatment methods for ischemic stroke, the mortality and disability rate have decreased significantly. At present, the main treatment methods for ischemic stroke include thrombolysis, thrombus removal at the ultra-early stage, and treatment of improving collateral circulation in the acute phase. However, the ultra-early and early blood reperfusion involves reperfusion injury, which will cause secondary nerve damage, which is called cerebral ischemia/reperfusion injury (CIRI). Studies have found that autophagy is involved in the entire process of CIRI and can reduce the damage of CIRI. The mammalian target of Rapamycin (mTORC1) is the primary signal pathway regulating autophagy. And the mTORC1 inhibitor, Rapamycin, has been proved to exert neuroprotective effects in the ultra-early and early cerebral ischemia-reperfusion. Therefore, screening and designing mTORC1 inhibitors is very important to control reperfusion injury and reduce neuronal death and apoptosis. In this research, plenty of computer-assisted was applied to virtually screen and select potential mTORC1's inhibitors. We used Libdock to screen the structure and performed toxicity predictions, ADME (absorption, distribution, metabolism, excretion) to predict small molecules' pharmacological and toxicological properties. To assess the binding mechanism and affinity between the mTORC1 dimer and the ligand, molecular docking was performed. Then, the pharmacophore of small molecules in the docking conformation with the protein was supplemented by Schrodinger. Additionally, molecular dynamics simulations were conducted to assess if the ligand-receptor complex was stable in a natural environment. Furthermore, an experiment was performed to verify the inhibitory effect of compound 1 and compound 2 on mTOR protein. All in all, the study provides a hand of candidate drugs as well as pharmacological properties, which can play an essential role in mTORC1 inhibitors.
