Deciphering the Neuroprotective Potential of Piperine Derivatives: A Computational Study

Alzheimer's disease (AD) is characterized by gradual and progressive neurodegeneration resulting from neuronal cell death. AD is a multifactorial condition associated with many known risk factors. In recent years, several studies have supported the involvement of the purinergic receptor (P2X7) in the pathology of Alzheimer's disease. Piperine is a potential antioxidant molecule. The neuroprotective actions of piperine have been demonstrated, but the precise role in the mechanism of neuroprotection remains unclear. In our current research, we designed a total of 23 semi‐synthetic piperine derivatives and conducted in silico studies against a homology‐built model of the P2X7 receptor. The catalytic molecular insights at the binding pocket were explored using in silico tools, including molecular docking, MM‐GBSA, ADMET, molecular dynamics simulation, and DFT Calculations. The docking protocol is validated by re‐docking the co‐crystal. Molecules with a higher glide score, ΔG Bind scores, exhibiting similar interaction profiles and showing moderate CNS activity, without any violations in Lipinski's rule of five, exhibited 100% human oral absorption. DFT calculations were conducted to study the electronic properties of top‐ranked molecules. The observations were further correlated through a 150 ns MD simulation. Results may provide a foundation for future investigations into managing neurodegenerative diseases like Alzheimer's.