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Integrative bioinformatics and drug repurposing for metastatic prostate cancer: identifying novel therapeutic targets
Haseeb Nisar1, Jignesh Prajapati2, Asma Muhammad Mumtaz3
1Interdisciplinary Research Centre for Finance and Digital Economy, King Fahd University of Petroleum & Minerals, Academic Belt Road Dhahran 31261, Eastern Province, Saudi Arabia.
Abstract:
Metastasis is one of the leading factors of cancer-related deaths worldwide. New potential targets and treatment strategies are needed to extend survival and enhance the quality of life for these patients. We performed an in-depth bioinformatics analysis to identify potential genes and associated potential therapeutic compounds for metastasis of prostate adenocarcinoma. The differentially expressed genes (DEGs) were first identified using four datasets (GSE8511), (GSE3325), (GSE27616) and (GSE6919) present in the Gene Expression Omnibus (GEO) database and analyzed using the GEO2R. WGCNA was performed to find a significant gene cluster. Network analysis was performed using MCODE and Cytohubba plugins of Cytoscape to select hub genes. Moreover, expression validation of key genes was carried out using the TCGA dataset. Functional annotation and pathway enrichment analyses were conducted for validation, while survival analysis was applied to assess potential therapeutic effects. DEGs retrieved from the GEO were submitted to the Connectivity Map database to identify potentially related compounds. Molecular docking, ADMET analysis and drug-likeness properties, MD simulations and MM-GBSA analysis were performed to screen for the best potential drugs. We identified three compounds-Prunetin, Ofloxacin, and ALW-II-49-7 that may help extend disease-free survival in patients with tumor metastasis. Additionally, ACTA2, MYLK, and CNN1 were recognized as potential therapeutic targets for these compounds. These drugs' potential effectiveness and binding efficiency were screened using induced fit molecular docking followed by 100 ns MD-based Simulations and MM-GBSA analysis. However, further in vitro and in vivo studies are needed to confirm these findings. Insight box This study integrates microarray gene expression profiling with bioinformatics tools to identify differentially expressed genes (DEGs) and co-expression networks using WGCNA. Network analysis in Cytoscape was used to screen hub genes, and the Connectivity Map (cMAP) database was searched for potential candidate drugs. Binding efficiency of repurposed drugs was evaluated using molecular docking, molecular dynamics (MD) simulations, and MM-GBSA analysis. Our findings provide the potential therapeutic drugs and targets of prostate adenocarcinoma metastasis with possibilities for follow-up in vitro and in vivo validation.
Insights
This study identifies potential drugs like Prunetin and Ofloxacin to treat prostate adenocarcinoma metastasis by targeting key genes. Further research is needed to confirm these findings for improved patient survival.
Area of Science:
- Oncology
- Bioinformatics
- Computational Biology
Background:
- Prostate adenocarcinoma metastasis is a major cause of cancer mortality.
- Novel therapeutic targets and strategies are crucial for improving patient outcomes.
Purpose of the Study:
- To identify potential therapeutic compounds and gene targets for prostate adenocarcinoma metastasis using bioinformatics.
- To evaluate the efficacy and binding efficiency of potential drugs through computational methods.
Main Methods:
- Differential gene expression analysis using GEO datasets and GEO2R.
- Weighted gene co-expression network analysis (WGCNA) and network analysis (Cytoscape).
- Drug screening via Connectivity Map, molecular docking, MD simulations, and MM-GBSA analysis.
Main Results:
- Identified three potential therapeutic compounds: Prunetin, Ofloxacin, and ALW-II-49-7.
- Identified ACTA2, MYLK, and CNN1 as potential therapeutic targets.
- Computational analyses confirmed the binding efficiency and potential effectiveness of the identified drugs.
Conclusions:
- Prunetin, Ofloxacin, and ALW-II-49-7 show promise for extending disease-free survival in prostate adenocarcinoma metastasis.
- ACTA2, MYLK, and CNN1 are potential therapeutic targets for these compounds.
- Further in vitro and in vivo studies are warranted to validate these computational findings.
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