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.