Structure-based identification and experimental evaluation of Oroxin A as a FYN kinase inhibitor

Fyn, a member of the Src family kinases (SFKs) and a non-receptor tyrosine kinase, plays a critical role in signal transduction within the nervous system and is instrumental in the activation and development of T lymphocytes. While the biological significance of Fyn kinase in various cellular processes is well recognized, its potential as a therapeutic target remains largely unexplored. In this study, we investigated the potential of natural products (NPs) as preferential inhibitors of Fyn kinase. A library of over 3500 NPs was screened for binding affinity with Fyn kinase (PDB: 2DQ7) using XGlide docking simulations. The fourteen NPs with the highest docking scores were selected for further analysis. Their interactions with Fyn kinase were evaluated through MM-GBSA calculations, and ADMET profiling was performed using SwissADME and pkCSM tools to assess pharmacokinetic properties. Molecular dynamics (MD) simulations using Desmond further confirmed the stability of FYN-NP complexes in solvent environments. Of the top fourteen NPs, only oroxin A demonstrated favorable drug-like properties and sustained stable binding to Fyn kinase, as evidenced by MD simulations. Moreover, in vitro kinase inhibition assays revealed that oroxin A exhibited dose-dependent inhibition of Fyn kinase. Additionally, C. elegans viability assays confirmed its low toxicity. Moreover, cross-docking revealed that although oroxin A binds to multiple SFKs due to conserved ATP binding pocket, it displayed stronger binding toward Fyn, suggesting binding preference over Fyn. This study provides a comprehensive evaluation of NPs as potential Fyn kinase inhibitors and identifies oroxin A as a natural compound with preliminary evidence of Fyn inhibition, warranting further validation.

FYN; FYN kinase and Oroxin A; In silico and ADMET; Molecular docking and dynamics simulation.