Unravelling Phyto-Compound Therapeutics against SRC Protein via FGF Pathway Targeting-A Comprehensive Approach Integrating Omics Data Analysis, Network Pharmacology, Virtual Screening, and Molecular Dynamics.

ABSTRACT

INTRODUCTION: Colorectal cancer is a complex condition influenced by genetic mutations and environmental factors. Due to its intricate nature, the diagnosis and treatment of this condition require a comprehensive approach that considers individual circumstances. The study aimed to identify genes linked with colorectal cancer and their therapeutic agents from natural bioactive compounds. METHODS: The significantly prognostic differentially expressed genes (DEGs) were screened out from NCBI Gene Expression Omnibus (GEO) datasets. A protein-protein interaction network was constructed using STRING Database, and key genes were identified using Network Analyzer and CytoNCA plugins within Cytoscape. Further analysis involved functional annotations, and biological pathways analysis, SRC mechanism to uncover the role of SRC in CRC. Additionally, we performed virtual screening and molecular docking, Physiochemical property analysis along with MD simulation study to propose suitable natural compounds for promising therapeutic targets. RESULTS: The study conducted differential gene expression analysis, identifying 3621 statistically significant genes, with 1467 upregulated and 2154 downregulated. The top ten genes with the highest degree, betweenness centrality, and closeness centrality in the PPI network were selected as key genes. The SRC gene was found to have the highest degree and closeness centrality. Functional annotation and pathway analysis of key genes with a specific focus on the SRC mechanism revealed that the SRC's role in activating the RAS-RAF-MEK-ERK and Wnt/ß-catenin pathways in CRC cells, promoting proliferation and invasion. Molecular modelling of SRC led to the screening of phyto-compounds from tropical fruits, with Rutinexhibiting a higher docking score compared to FDA-approved anticancer drugs. MD simulations over 100 ns and the post-MD analysis i.e. RMSD, SASA, RMSF, FEL, RG, Hydrogen bond, PCA, and MMPBSA, comprehended the stable and robust interactions of a protein-ligand complex. These findings suggest Rutin's potential as a potent natural molecule for treating CRC. The study concludes that SRC plays a pivotal role in CRC, influencing cellular processes critical to cancer development and Rutin has been found to be a promising SRC inhibitor, suggesting a potential alternative therapeutic strategy for CRC. The consistent molecular interactions of Rutin necessitate further validation through wet lab experiments, offering hope for individuals affected by CRC.