## 4 Discussion
One pathway containing many protein molecules modulated by one compound is more essential than the function of one protein that involves many pathways modulated by one drug molecule. The impact of one target in numerous pathways may be less, and the impact of one pathway with multiple protein targets modulated by one compound could be large [48]. Based on this theory, we chose 11 phytocompounds, viz., Andrographine C, 5-Hydroxy-7,8,2\({}^{\prime}\)-Trimethoxyflavone (Andrographin), Skullcapflavone 1, 2\({}^{\prime}\)-hydroxy-5,7,8-trimethoxyflavone, 5,4\({}^{\prime}\)-dihydroxy-7,8,2\({}^{\prime}\),3\({}^{\prime}\)-tetramethylflavone, 5-hydroxy-7,8-dimethoxyflavone, 5-hydroxy-7,8,2\({}^{\prime}\),5\({}^{\prime}\)-tetramethylflavone, 5-hydroxy-7,8,2\({}^{\prime}\),3\({}^{\prime}\),4\({}^{\prime}\)-pentamethoxyflavone, Wightin, 5-Hydroxy-7,8,2\({}^{\prime}\),3\({}^{\prime}\)-Tetramethoxyflavone, and Altisin from _A. paniculata_ (are of Andrographide derivatives) contained in _A. paniculata_ whole plant and Gossypetin, Herbacetin, and Kaempfer-7-Glucoside contained in _T. populnea flowers_[49]. These phytocompounds were identified as flavonoids and triterpenoids and were found to modulate thirteen protein molecules involved in the progression of HBV infection to HCC, i.e., CDK1, CDK2, CDK6, EGFR, HGF, IGF1R, TERT, STAT3, PRKCA, PRKCB, PRKCG, AKT1, and TNF. Further, these protein targets were also found to modulate 14 major molecular pathways, i.e., Hepatitis B pathway, hepatocellular carcinoma, MicroRNAs in cancer, MAPK signaling pathway, PI3K-Akt signaling pathway, Ras signaling pathway, mTOR signaling pathway, apoptosis, viral carcinogenesis, TNF signaling pathway, Jak-STAT signaling pathway, p53 signaling pathway, and cell cycle. The roles of each protein target associated with the identified pathways involved in the pathogenesis of HBV infection and progression of HCC are shown in Table S8. After gene ontology, enrichment, and network analysis, we further extended the study to examine the intermolecular interactions between phytocompounds and predicted protein targets using docking and MD simulation studies. As a result, we have chosen EGFR, as it earned the top-scoring node with the highest edge count of 29. Thus, this formed the sole rationale for the initial blind selection of EGFR as a potential target. On secondary literature analysis, it was found to be well documented as a therapeutic target for cancer (identified to be involved in the MAPK, PI3-Akt, Ras, and Jak-STAT signaling pathways within the network). Moreover, earlier studies have demonstrated that overexpression of EGFR is common in HCC, meaning that it can play a role in the pathogenesis and treatment of the disease. Hence, on cumulative analysis of blind network topology prediction and the documented studies, EGFR was finalized as the most potential target. It is well known that NTCP host receptors are essential for HBV entry. However, NTCP expression alone is not enough for the entry of HBV. EGFR is a host cofactor that regulates the host cell's ability to support HBV internalization and is essential for NTCP's viral receptor activity [50]. After HBV binds to NTCP on the cell surface, the HBV-NTCP complex is internalized via EGFR endocytosis machinery, which includes EGFR phosphorylation and the subsequent recruitment of adaptor molecules such as \"AP2A1 and EPS15\" [51; 52; 53]. The EGFR-sorting machinery (involving EGFR ubiquitination, STAM, and LAPTM4B) coordinates HBV transport in the endosomal network (early and late endosome and lysosome) [51]. In addition, researchers examined the EGF-related host factor(s) in HBV infection by siRNA-mediated knockdown of endogenous EGFR in HepG2-NTCP cells, HepaRG cells, and primary human hepatocytes and observed a significant reduction in HBV infection. The researchers reported that HBV viral attachment was not decreased in EGFR-knockdown cells, but the level of HBV DNA internalized into cells was significantly reduced by knockdown of EGFR [52].