Computational Prediction of Ginsenosides Targeting ADGRG3/GPR97 in Cancer and Immune Pathways: A Multi-Faceted In Silico Approach

Ginsenosides are bioactive secondary metabolites in ginseng, which have gained popularity for their usage in traditional Oriental medicine. Many studies have reported that ginsenosides exert their effects through multiple pathways, such as GPCR-related pathways. However, focusing on their specific interactions with ADGRG3 (GPR97) can provide possible insights to inform targeted intervention strategies in oncology and immunotherapy through the tumor–immune microenvironment interactions. Thus, this study employed an integrative in silico computational strategy to investigate ginsenosides as possible targets of ADGRG3. First, gene expression was analyzed using multiple databases such as TCGA, cBioPortal, and TIMER, revealing the differential expression of ADGRG3 across cancers, with notable overexpression in leukemia. Then, the virtual screening of 128 ginsenosides identified five top candidates (Rg3, Rk3, F5, Rg7, and F1) that showed strong binding energy (−10.7 −10.6, −10.5, −10.4, and −10.3 kcal/mol, respectively) with ADGRG3, as determined through in silico molecular docking (MD). Computational approaches such as molecular dynamics simulations (MDSs), free binding energy calculations (MM-PBSA), and ADMET profiling confirmed the stability of these complexes’ favorable ADMET predictions, respectively, which warrants further experimental validation through in vitro and in vivo pharmacokinetic studies. Finally, the computational protein–protein interaction and pathway enrichment analyses of ADGRG3 demonstrated immune-related pathways, such as neutrophil degranulation and GPCR signaling, emphasizing its role in cancer progression and immune modulation. These computational findings predict ADGRG3 as a viable target for cancer and immune pathways and ginsenosides as natural ligands. Further in vitro and in vivo preclinical and clinical studies are warranted to validate the interactions of ADGRG3 with ginsenosides.