NDs tend to share some characteristics such as memory loss and the aggregation of abnormal proteins. Literally, hundreds of neurological/neurodegenerative diseases have been identified, but some like Alzheimer’s disease (AD) and Parkinson’s disease (PD) are very well known and have devastating impacts in modern society. Neurological disorders (NDs) are usually due to structural and/or functional losses of neurons and eventually neuronal death. We suggest that the inhibitory efficacies of ZINC19370490 and ZINC04534268 be subjected to experimental validation. Furthermore, their physical properties were found to be acceptable, and they are non-toxic according to the ADMET online server. MM-PBSA analysis showed that these compounds were comparable or better than reported caspase 8 inhibitors. These compounds were stable throughout simulations and interacted with targeted protein by forming hydrogen and van der Waal bonds. Screening generated 5332 candidates, but after applying stringent criteria only two candidate compounds, ZINC19370490 and ZINC04534268, were evaluated by molecular dynamics simulations and subjected to Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) analysis. Based on the structural information of reported inhibitors, we designed several individual and consensus pharmacophore models and then screened the ZINC database, which contains 105,480 compounds. To extend the repertoire of caspase 8 inhibitors, we employed several computational approaches to identify potential caspase 8 inhibitors. Thus, blocking the activity of caspase 8 is considered a potential therapy for neurodegenerative diseases. The critical role of this protease in cell death pathways has generated research interest because its activation has also been linked with neural cell death.
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Caspase 8 is a central player in the apoptotic cell death pathway and is also essential for cytokine processing.
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