Background: Apoptosis of brain cells (neurons and glia) has a crucial role in humans' pathology of traumatic brain injury (TBI). So, a decrease in the apoptosis rate can potentially reduce the harmful effects and lead to better functional outcomes. Drug repurposing by computational methodologies like protein-ligand docking allows us to make drug discovery more efficient and less expensive.
Objective: In the current study, we used the methodology to study the inhibitory effect of thousands of FDA/non-FDA approved, investigational compounds on caspase 3 as one of the most important members of the cell apoptosis pathway.
Methods: Molecular docking and pharmacokinetic properties calculations were done. The molecular dynamics (MD) simulations of all complexes and free caspase 3 were carried out. We carried out docking experiments using in silico methods and docked a pool of medications to the active site of the human caspase-3 X-ray structure. The best compounds were selected and subjected to pharmacokinetic analysis, molecular simulation, and free energy calculations.
Results: Finally, 6 components (Naldemedine, Celastrol, Nilotinib, Drospirenone, Lumacaftor, and R- 343) were selected as the best in terms of structural and pharmaceutical properties, low toxicity that can be administered orally for the preclinical and clinical future investigations.