Bioinformatic Approaches to Identify Novel Sphingosine Kinase-1 Inhibitors from Fungal Bioactives for Cancer Therapy

Abstract

Background: Sphingosine kinase 1 (SphK1) is a crucial oncogenic lipid kinase responsible for regulating the sphingolipid balance. It plays a key role in apoptosis, cell growth, proliferation, inflammation, migration, signal transduction, metabolism, and cancer progression. Overexpression of SphK1 is observed in cancer, making it a potential target for cancer treatment and other diseases. Our study aimed to identify novel fungal bioactives with possible anti-SphK1 activity using in-silico approaches. Methods: The bioactives absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were determined, and molecular docking was conducted with the target protein. Protein-protein interactions, gene enrichment analysis, and comprehensive topological properties of selected protein were also assessed. Furthermore, we evaluated the molecular dynamics simulation (MDs) of the top-docked protein-ligand complex. Results: All the compounds selected for the present study met the criteria for drug-like characteristics and adhered to Lipinskis rule of five (RO5). The Molecular binding results showed that Cytochalasin H was the most significant molecule, displaying a binding affinity of –11.1 kcal/mol. The search tool for the retrieval of interacting genes/proteins (STRING) database provided insights into the protein-protein network interactions. This studys enrichment analysis indicated that the differentially expressed genes were significantly enriched in sphingolipid metabolism, followed closely by the vascular endothelial growth factor (VEGF) signaling pathway. Computed atlas of surface topography of proteins (CASTp) analysis revealed the topographic properties of SphK1 protein, with the top pocket having an area accessible surface (AS) of 7119.22 Ų and volume accessible surface (AS) of 7762.45 ų. The MDs analysis showed increased root mean square deviation (RMSD) and radius of gyration (Rg) values, indicating significant conformational alterations during the simulation period. Conclusions: This study suggests that cytochalasin H may be repurposed as a potential SphK1 inhibitor. These findings could be clinically relevant for the development of therapeutic drugs.