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. 2024 Oct;28(20):e70133.
doi: 10.1111/jcmm.70133.

Elucidating gastric cancer mechanisms and therapeutic potential of Adociaquinone A targeting EGFR: A genomic analysis and Computer Aided Drug Design (CADD) approach

Mariam Abdulaziz Alkhateeb  1 , Nada H Aljarba  1 , Qudsia Yousafi  2 , Fatima Anwar  2 , Partha Biswas  3
Affiliations

Elucidating gastric cancer mechanisms and therapeutic potential of Adociaquinone A targeting EGFR: A genomic analysis and Computer Aided Drug Design (CADD) approach

Mariam Abdulaziz Alkhateeb et al. J Cell Mol Med. 2024 Oct.

Abstract

Gastric cancer predominantly adenocarcinoma, accounts for over 85% of gastric cancer diagnoses. Current therapeutic options are limited, necessitating the discovery of novel drug targets and effective treatments. The Affymetrix gene expression microarray dataset (GSE64951) was retrieved from NCBI-GEO data normalization and DEGs identification was done by using R-Bioconductor package. Gene Ontology (GO) analysis of DEGs was performed using DAVID. The protein-protein interaction network was constructed by STRING database plugin in Cytoscape. Subclusters/modules of important interacting genes in main network were extracted by using MCODE. The hub genes from in the network were identified by using Cytohubba. The miRNet tool built a hub gene/mRNA-miRNA network and Kaplan-Meier-Plotter conducted survival analysis. AutoDock Vina and GROMACS MD simulations were used for docking and stability analysis of marine compounds against the 5CNN protein. Total 734 DEGs (507 up-regulated and 228 down-regulated) were identified. Differentially expressed genes (DEGs) were enriched in processes like cell-cell adhesion and ATP binding. Eight hub genes (EGFR, HSPA90AA1, MAPK1, HSPA4, PPP2CA, CDKN2A, CDC20, and ATM) were selected for further analysis. A total of 23 miRNAs associated with hub genes were identified, with 12 of them targeting PPP2CA. EGFR displayed the highest expression and hazard rate in survival analyses. The kinase domain of EGFR (PDBID: 5CNN) was chosen as the drug target. Adociaquinone A from Petrosia alfiani, docked with 5CNN, showed the lowest binding energy with stable interactions across a 50 ns MD simulation, highlighting its potential as a lead molecule against EGFR. This study has identified crucial DEGs and hub genes in gastric cancer, proposing novel therapeutic targets. Specifically, Adociaquinone A demonstrates promising potential as a bioactive drug against EGFR in gastric cancer, warranting further investigation. The predicted miRNA against the hub gene/proteins can also be used as potential therapeutic targets.

Keywords: CMNPD; hub genes; miRNA; molecular docking; survival analysis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Phosphorylation dependent and independent pathway through CagA. CagA cytotoxin associated gene follows two pathways for causing cellular proliferation which is one is (A) phosphorylation independent pathway in which it triggers AKT pathway (also known as protein kinase B or PKB) leading to p53 proteasomal degradation, which leads to cellular proliferation and ultimately to gastric cancer. (B) Phosphorylation dependent pathway which follows the MAP (mitogen‐activated protein) kinase pathway which also leads to cellular proliferation and ultimately to gastric cancer (Source: Sonkar et al., 2022.
FIGURE 2
FIGURE 2
Three‐dimensional structure of chain A of EGFR kinase domain (PDB ID: 5CNN).
FIGURE 3
FIGURE 3
Number of DEGs of gastric cancer (GSE64951) involved in GO categories. (A) Biological processes (B) Molecular Function (C) Cellular components.
FIGURE 4
FIGURE 4
Protein–protein interaction network and network sub‐clusters (modules) for DEGs gastric cancer (GSE64951). Here Green nodes = downregulated genes; Red nodes = upregulated genes.
FIGURE 5
FIGURE 5
Pathway Enrichment network for DEGs (GSE64951) in top three sub‐clusters of PPI network.
FIGURE 6
FIGURE 6
Gene association network of hub genes from gastric cancer DEGs dataset GSE64951. Black nodes = hub genes; Grey nodes = result (associated) genes.
FIGURE 7
FIGURE 7
mRNA ‐miRNA network for the hub genes of dataset GSE64951.
FIGURE 8
FIGURE 8
Kaplan–Meier‐Plots for survival analysis of hub genes from the gastric cancer DEGs dataset GSE64951. (A) PP2CA. (B) EGFR. (C) CDKN2A. (D) MAPK1. (E) HSP90AA1. (F) HPSP4. (G) ATM (H) CDC20.
FIGURE 9
FIGURE 9
Boxplots for the expression of hub genes in gastric cancer (dataset GSE64951). (A) CDKN2A. (B) EGFR. (C) PP2CA. (D) HSP90AA1. (E) MAPK1. (F) HPSP4. * represents the significant expression status.
FIGURE 10
FIGURE 10
Adociaquinone A‐5CNN 2D & 3D interactions at different poses during Molecular dynamics simulation run at 50 ns. Here, (A) 10 ns, (B) 20 ns, (C) 30 ns, (D) 40 ns, (E) 50 ns.
FIGURE 11
FIGURE 11
Comparison of different poses of interaction in Adociaquinone A‐5CNN complex during Molecular dynamics simulation run at 50 ns. (A) Superposed poses of complex (B) Tiled poses of complex (ligand in blue).
FIGURE 12
FIGURE 12
Molecular dynamics simulation graphs run at 50 ns for Adociaquinone A‐5CNN docked complex. (A) Total system energy. (B) Hydrogen bonds. (C) Radius of gyration. (D) Root means square deviation (RMSD). (E) Radial distribution function. (F) Root means square function (RMSF). (G) Solvent accessible surface area.
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References

    1. Parsonnet J, Vandersteen D, Goates J, Sibley RK, Pritikin J, Chang Y. Helicobacter pylori infection in intestinal‐ and diffuse‐type gastric adenocarcinomas. J Natl Cancer Inst. 1991;83:640‐643. doi:10.1093/jnci/83.9.640 - DOI - PubMed
    1. Coggon D, Barker DJ, Cole RB, Nelson M. Stomach cancer and food storage. J Natl Cancer Inst. 1989;81:1178‐1182. doi:10.1093/jnci/81.15.1178 - DOI - PubMed
    1. Rahman MA, Rahman MDH, Hossain MS, et al. Molecular insights into the multifunctional role of natural compounds: autophagy modulation and cancer prevention. Biomedicine. 2020;8:517. doi:10.3390/biomedicines8110517 - DOI - PMC - PubMed
    1. Baral SK, Biswas P, Kaium MA, et al. A comprehensive discussion in vaginal cancer based on mechanisms, treatments, risk factors and prevention. Front Oncol. 2022;12:883805. doi:10.3389/fonc.2022.883805 - DOI - PMC - PubMed
    1. Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144:1941‐1953. doi:10.1002/ijc.31937 - DOI - PubMed

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