In-silico screening to identify phytochemical inhibitor for hP2X7: A crucial inflammatory cell death mediator in Parkinson's disease.

The second most prevalent neurological disease among the elderly is Parkinson's disease, where neuroinflammation plays a significant role in its pathology. Purinergic signaling mediated by P2X7 plays a significant role in neuroinflammation and pyroptotic cell death pathways through mediators like NLRP3, Caspase-1, and Caspase-3, instigating pyroptotic cell death. No synthetic agent advanced in late-stage clinical trials due to their inefficacy and toxicity. Hence, in this study, we aimed to identify a phytoconstituent inhibitor against the hP2X7 receptor to ameliorate the inflammatory processes involved. To achieve this aim, we performed homology modeling of the receptor and screened phytoconstituents from a library of over 3500 commercially available phytoconstituents. Molecular docking through the Maestro program of the Schrödinger suite was performed considering evaluation parameters like docking score, docking pose and spatial arrangement, and MMGBSA binding free energy. Predictive pharmacokinetic and toxicity profiling was done using tools like QikProp, ADMETLab 2.0, SwissADME, and Protox-II. Molecular dynamic simulation was performed using Schrödinger's Desmond tool for the top 10 phytoconstituents. The complex stability was evaluated based on the ligand- and protein-RMSD, protein-ligand contact stability over a simulation period of 100 ns, protein RMSF, and ligand properties like RMSF, radius of gyration, intramolecular hydrogen bonding, and SASA. Based on the studies' results, silychristin, silybin, rosmarinic acid, nordihydroguaiaretic acid, and aurantiamide were shortlisted as the top 5 phytoconstituents against hP2X7. Further in-vitro and in-vivo studies would offer better clarity on the mechanism of action of these agents specifically related to pyroptotic cell death in various disease models.