An in-silico study to identify potent phytochemicals for reducing neurotoxicity triggered by calpain and CDK5/p25 complex.

Cyclin-dependent kinase 5 (CDK5) plays a critical role in various neural processes. When aberrantly activated through its association with p25 (calpain-cleaved fragment of p35), it causes several types of neurodegenerative diseases. This study aimed to identify potent phytochemical inhibitors of CDK5/p25 and calpain using in silico techniques. A library of 750 phytochemicals was initially screened from Dr. Duke's Phytochemical and Ethnobotanical Database. After ADMET profiling, 90 compounds were selected for molecular docking. Among these, strobopinin exhibited the highest binding affinity for both CDK5/p25 (-8.84 kcal/mol) and calpain (-6.74 kcal/mol), outperforming the control inhibitors with binding affinities of -7.9 and -6.6 kcal/mol, respectively. Molecular dynamics simulations over 100 ns confirmed the stability of strobopinin-CDK5/p25 complex, with RMSD values ranging between 0.5 and 0.75 nm. In contrast, the strobopinin-calpain complex exhibited higher fluctuations, reaching up to 1.5 nm, indicating a lower stability. Density functional theory calculations revealed a HOMO-LUMO energy gap reduction from 0.166 eV to 0.159 eV for the calpain complex, indicating increased chemical reactivity compared to the CDK5/p25 complex. These findings suggest that strobopinin may act as a dual inhibitor, mitigating CDK5/p25 hyperactivation and calpain-mediated neurotoxicity. This dual inhibition positions strobopinin as a promising candidate for neuroprotective therapy, offering a comprehensive approach to target two major neurotoxic pathways. Further experimental validation is required to confirm these findings and assess clinical viability, which could lead to novel, phytochemical-based treatment strategies for neurodegenerative diseases.