Effects of naphthoquinone scaffold-derived compounds on head and neck squamous cell carcinoma based on network pharmacology and molecular docking

Abstract

Objectives: This study aimed to analyze the effects of naphthoquinone scaffold-derived compounds on head and neck squamous cell carcinoma (HNSCC) using network pharmacology and molecular docking.

Methods: We screened candidate compounds from the ASINEX database and evaluated their drug likeness and toxicity. They identified 80 compounds with naphthalenone structures, focusing on 1,4-naphthoquinone and 1,2-naphthoquinone scaffolds. The possible targets of these compounds were predicted using databases like SwissTargetPrediction and Similarity Ensemble Approach Database (SEA).

Results: The common targets between the compounds and HNSCC were identified, yielding 65 overlapping targets. A protein-protein interaction (PPI) network was constructed, and 20 hub genes were identified based on centrality metrics. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that these compounds' protective effects against HNSCC are associated with cancer-related pathways, such as those in cancer and proteoglycans in cancer. Molecular docking was performed to evaluate the binding affinity between the compounds and hub genes. The results showed that the compounds had strong binding affinities with key targets like MET and TYK2, with binding energies < -5 kcal/mol.

Conclusions: The study suggests that naphthoquinone derivatives could serve as novel chemotherapy agents for HNSCC, warranting further research for clinical application.

Keywords: Naphthoquinone; head and neck squamous cell carcinoma; molecular docking; network pharmacology; virtual screening.

Figure 1

The eight compounds selected.

Figure 2

Compound targets and HNSCC targets. A: Venn diagram of predicted compound targets from the database and HNSCC differentially expressed genes downloaded from the Gepia website. B: PPI of the intersecting target genes, with hub genes represented by yellow nodes.

Figure 3

Topological analysis of the PPI. A: The first cluster obtained using the MCODE algorithm. B: The second cluster obtained using the MCODE algorithm. C: The third cluster obtained using the MCODE algorithm. D: PPI of hub genes.

Figure 4

GO enrichment analysis, KEGG pathway analysis of hub genes. A: Biological processes of GO enrichment analysis. B: Molecular function of GO enrichment analysis. C: Cellular components of GO enrichment analysis. D: KEGG pathway analysis.

Figure 5

Topological structure diagram of Pathways in cancer.

Figure 6

Compounds-target-pathway-disease network.

Figure 7

Molecular docking heat map of naphthoquinone scaffold-derived compounds and core targets.

Figure 8

Molecular docking results between the compound and target. A: Analysis of protein-ligand interactions between compound 7 and MET. The numbers indicate the locations of the four hydrogen bonds, which are at THR-138, SER-139, GLN-145, and ARG-149, respectively. B: Analysis of protein-ligand interactions between compound 8 and TYK2. The image indicates the location of the halogen bonds. C: Three-dimensional molecular docking graph between compound 7 and MET. D: Three-dimensional molecular docking graph between compound 8 and TYK2.

Figure 9

Overall survival analysis of core gene in the UALCAN database.

Figure 10

Final step of the synthetic route of compounds. A: Synthetic route of compound 7 from Reaxys. B: Synthetic route of compound 8 from Reaxys. C: Synthetic route of compound 6 from AiZynthFinder. D: Synthetic route of compound 7 from AiZynthFinder.