In-silico analysis reveals the core targets and mechanisms of CA028, a new derivative of calycosin, in the treatment of colorectal cancer

Abstract

BackgroundColorectal cancer (CRC) is a type of malignant gastroenteric tumors associated with a high mortality rate worldwide. Calycosin, a natural phytoestrogen, possesses potent anti-cancer properties. We structurally modified calycosin to improve its physicochemical properties, and generated a novel small molecule termed CA028. MethodsBy using network pharmacology, followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis and molecular docking, we aimed to predict and disclose the biological functions and mechanism of CA028 in the treatment of CRC through bioinformatic analyses. ResultsBy searching the online Swiss Target Prediction and TargetNet databases, we identified 150 genes shared by CA028 and CRC. Using the Search Tool for the Retrieval of Interacting Genes (STRING) database and Cytoscape software, we identified 14 hub-functional genes, namely the FYN proto-oncogene, a Src family tyrosine kinase (FYN), mitogen-activated protein kinase 1 (MAPK1), MAPK8, MAPK14, Rac family small GTPase 1 (RAC1), epidermal growth factor receptor (EGFR), protein tyrosine kinase 2 (PTK2), sphingosine-1-phosphate receptor 1 (S1PR1), S1PR2, Janus kinase 1 (JAK1), JAK2, the RELA proto-oncogene NF-κB subunit (RELA), bradykinin receptor B1 (BDKRB1), and BDKRB2. Additionally, biological docking analysis using the Autodock Vina software revealed that FYN and MAPK1 were the main pharmacological proteins of CA028 against CRC. The gene ontology analysis using R-language packages further revealed the anti-CRC functions of CA028, including biological processes, cell components, and molecular pathways. ConclusionCA028 exhibits effective pharmacological activity against CRC by suppressing the proliferation of CRC cells and improving the tumor microenvironment. Importantly, certain predicted genes (e.g., FYN and MAPK1) may be the pharmacological targets of CA028 in the treatment of CRC.