## 1 Introduction
These natural substances have presented cytotoxicity against tumor cells and efficacy in preclinical studies, influencing intracellular signaling pathways involved in cancer [27; 28; 29; 30; 31; 32]. Research has shown that triterpenoids influence multiple intracellular signaling pathways, exhibiting chemopre and antitumor properties in various cancer models [33]. For instance, oleanolic acid derivatives modulated proliferation, apoptosis, and inflammation in breast cancer, while misletoe triterpenoids enhanced melanoma treatment outcomes in animal models [34]. However, challenges such as poor solubility and bioavailability limit their development [35; 36]. Future studies should prioritize systematic target identification and structure-activity relationship analyses to optimize their therapeutic potential. Among triterpenoids, ginseng from Panax species are promising due to their multitarget abilities, steroid-like structures, and favorable properties [37; 38; 39; 40]. Despite these advantages, research on ginseng faces challenges, including structural diversity (over400 isoforms) and varying efficacy between major and minor ginsengosides. Moreover, ginseng have demonstrated anti-inflammatory and anticancer properties, and their structural similarities to synthetic steroids such as dexamethasone reinforce their potential to modulate GPCRs [41,42]. Adhesion GPCRs (a GPCRs) play a key role in tumor microenvironment modulation, immune cell trafficking, and tumor progression. They have long extracellular domains that facilitate interactions with the extracellular matrix, influencing cell adhesion, migration, and invasion--processes that are critical in cancer. Moreover, many GPCRs signal through classical G\(\alpha\) proteins (Gs, Gi, Gq, and G12/13). ADGRG3 shows unique autoproteolysis-dependent signaling (via the GPS motif); can influence multiple pathways, such as cAMP regulation, RhoA activation, and NF-\(\kappa\)B signaling; and specifically allows for targeted analysis of its non-canonical pathways. However, ginseng-sides' specific interactions with ADGRG3 remain unexplored, presenting an opportunity to investigate these natural compounds as modulators with potentially safer profiles than synthetic drugs [42, 43, 44, 45]. In recent years, computational biology has transformed drug discovery by integrating in silico molecular docking (MD), molecular dynamics simulations (MDSs), and ADMET predictions with gene expression and pathway analyses [44, 46, 47, 48, 49, 50]. In silico technologies such as MD and MDS are well-known examples of virtual screening techniques based on a structure, and these have been proven important in elucidating the relationships between biomolecules [51]. These methods provide reliable predictable insights into target-ligand interactions while reducing experimental time and cost. Additionally, publicly available datasets, such as those from TCGA and cBioPortal, further enhance research by offering comprehensive gene expression, mutation, and survival data to validate therapeutic targets in cancer and inflammation. This study employed a multi-step in silico approach to assess ginseng as natural ligands of ADGRG3. First, gene expression analyses using TCGA, cBioPortal, UALCAN, and TIMER validated ADGRG3's relevance in cancer and immune pathways. Next, 128 ginseng and four control ligands (becomethasone dipropionate, dexamethasone, HCV, and prednisolone) were screened for their ability to bind to ADGRG3 through in silico MD. Becomethasone dipropionate is an approved drug that acts as an agonist against ADGRG3 ([[https://www.gencards.org/cgi-bin/carddisp.pl?gene=ADGRG3](https://www.gencards.org/cgi-bin/carddisp.pl?gene=ADGRG3)]([https://www.gencards.org/cgi-bin/carddisp.pl?gene=ADGRG3](https://www.gencards.org/cgi-bin/carddisp.pl?gene=ADGRG3)) #drugs_compounds, accessed on 25 April 2023 and 20 February 2025). Computational ADMET analysis was conducted to evaluate pharmacokinetics, while MD simulations assessed binding stability.