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Identification of prostate cancer potential therapeutic targets and virtual drug screening through combined Mendelian
Zilong Liang1,2, Conglei Hu1, Haofeng Pang1
1Department of Urology, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China.
Background:
Prostate cancer (PCa) faces significant global challenges, including rising incidence and drug resistance. Our research aims to identify novel protein targets for innovative treatments, evaluate potential adverse effects, and find compounds with strong binding affinity.
Methods:
We conducted a proteomic Mendelian randomization (MR) study to assess the causal relationship between plasma proteins and PCa risk. Plasma protein data were obtained from the UK Biobank Pharmaceutical Proteomics Project, which includes GWAS data for 2940 plasma proteins. The PCa GWAS data were sourced from the PRACTICAL Consortium me-ta-analysis, encompassing 79,148 patients and 61,106 controls. Plasma proteins with positive MR results were further analyzed for Bayesian colocalization, druggability, and stratification. We performed a phenome-wide association study (PheWAS) on first and second tier proteins and screened first tier proteins against TS Biochem's library of 2070 anti- PCa com-pounds using molecular docking.
Results:
The MR study revealed five plasma proteins as protective factors and nine as risk factors for PCa (PFDR < 0.05). Subsequent analyses identified SCP2 (OR: 2.10, 95% CI:1.45-3.03, PFDR = 0.027) and C5 (OR: 1.23, 95% CI:1.10-1.37, PFDR = 0.037) as promising drug targets. Molecular docking showed beta-Amyrone exhibited strong binding energy with both SCP2 and C5 (binding energies of - 9.2 kcal/mol and - 8.9 kcal/mol, respectively), suggesting its potential as a dual-target inhibitor.
Conclusion:
Our study identified several protein biomarkers associated with PCa risk and screened potential compounds using molecular docking. These findings provide new insights and promising targets for PCa drug development, with beta-Amyrone showing strong potential as a dual-target inhibitor against both C5 and SCP2.
Insights
This study identifies novel protein targets and compounds for prostate cancer (PCa) treatment. Beta-amyron shows potential as a dual-target inhibitor for SCP2 and C5, offering new avenues for PCa drug development.
Area of Science:
- Genetics and Proteomics
- Cancer Research
- Drug Discovery
Background:
- Prostate cancer (PCa) presents growing global challenges, including increased incidence and resistance to existing therapies.
- Identifying novel protein targets and effective compounds is crucial for developing innovative PCa treatments.
Purpose of the Study:
- To identify novel protein targets for prostate cancer (PCa) treatment.
- To evaluate potential adverse effects and discover compounds with strong binding affinity.
- To assess the causal relationship between plasma proteins and PCa risk.
Main Methods:
- Proteomic Mendelian randomization (MR) study using UK Biobank and PRACTICAL Consortium GWAS data.
- Bayesian colocalization, druggability assessment, and phenome-wide association study (PheWAS) for identified proteins.
- Molecular docking screening of identified proteins against a library of anti-PCa compounds.
Main Results:
- MR analysis identified five protective and nine risk plasma proteins for PCa.
- SCP2 and C5 were highlighted as promising drug targets with significant associations.
- Beta-amyron demonstrated strong binding affinity to both SCP2 and C5, indicating potential as a dual-target inhibitor.
Conclusions:
- Several protein biomarkers associated with PCa risk were identified.
- Beta-amyron emerged as a promising dual-target inhibitor candidate for PCa therapy.
- Findings offer new insights and potential targets for advanced prostate cancer drug development.
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