Exploring the therapeutic potential of Emblica officinalis natural compounds against hepatocellular carcinoma (HCC): a computational approach

Abstract

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer related deaths globally. Despite advancements in treatment, drug resistance and adverse side effects have spurred the search for novel therapeutic strategies. This study aimed to investigate how the Emblica officinalis can inhibit key targets involved in HCC progression. Screening of the reported compounds based on ADMET profile and identification of protein targets was done using the literature survey. Protein targets were divided into four major categories including inflammatory, angiogenic, anti-apoptotic as well as proliferative targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to reveal the functional roles of genes. The STRING database was used to analyze the protein-protein interactions (PPI) of target genes. Docking was employed to predict the binding affinity of compounds with target proteins. Subsequently, MD simulation was conducted to assess the stability and dynamics of protein-ligand complexes. A total of 22 active compounds with 25 protein targets have been identified. These targets have a major role in controlling biological processes such as apoptosis, signaling and cellular interactions. KEGG pathway analysis showed that cancer, atherosclerosis, PI3K-Akt, EGFR tyrosine kinase inhibitor resistance and MAPK signaling pathways are mainly involved. Molecular docking by Mcule platform demonstrated that emblicanin A, punigluconin, penta-o-galloylglucose and quercetin showed higher binding energy affinities with BCL2, BCL2L1, c-Met, HSP70, EGFR, FGFR1, PTGS2 and TNFα. MD simulation revealed conformational changes, flexibility, interactions and compactness of protein-ligand complex. The stable protein binding interactions suggest the potential of compounds to inhibit the functions of target proteins. These results suggest that compounds derived from E. officinalis may have the therapeutic potential for treating HCC. See also the graphical abstract(Fig. 1).

Keywords: MD simulation; angiogenesis, docking; hepatocellular carcinoma (HCC); natural compounds.

Table 1. Predicted drug-likeness properties of potential compounds from E. officinalis

Table 2. List of HCC protein targets with their PDB IDs and biological significance

Table 3. E. officinalis compounds with multiple protein targets with pathways involved in HCC

Table 4. Top compounds of E. officinalis with binding affinities (kcal/mol) selected for MD Simulations

Table 5. Protein-ligand interactions of EGFR and FGFR1

Figure 1. Graphical abstract

Figure 2. Classification of HCC protein targets

Figure 3. Network analysis of (a) compounds and target proteins where blue: herb, green: ingredient, red: gene and yellow: disease; (b) PPI network of proteins constructed by using STRING https://www.string-db.org/ database

Figure 4. GO enrichment analysis and KEGG analysis of the protein targets for the treatment of HCC with E. officinalis

Figure 5. E. officinalis compounds such as emblicanin A (brown circle), penta-o-galloylglucose (purple circle), punigluconin (red circle) and quercetin (green circle) can target EGFR, c-Met, and VEGFR

Figure 6. Molecular docking of HCC protein-ligand complexes and 2D and 3D visualization by Discovery Studio. Core targets EGFR with (a) emblicanin A, (b) penta-o-galloylglucose, (c) punigluconin, (d) quercetin and FGFR1 with (e) emblicanin A, (f) penta-o-galloylglucose, (g) punigluconin and, (h) quercetin

Figure 7. Molecular dynamics simulation of EGFR-ligand during the 200 ns time period. Analysis of RMSD, RMSF, Rg and hydrogen bond plots reveal insights into the structural stability, flexibility, compactness and intermolecular interactions

Figure 8. Molecular dynamics simulation of FGFR1-ligand during the 200 ns time period. Analysis of RMSD, RMSF, Rg and hydrogen bond plots reveal insights into the structural stability, flexibility, compactness and intermolecular interactions