Characterizing high-risk SPOP mutations in prostate cancer: Insights from computational analysis and protein-ligand docking

Prostate cancer is a prevalent form of male malignancy in the urogenital tract and a significant cause of mortality globally. It can be asymptomatic in its earliest phases and often has a slow progression that only requires regular monitoring. According to GLOBOCAN 2018 estimates, there were 1276,106 new cases of prostate cancer recorded globally in 2018. The development and advancement of cancer depend on genetic mutations in specific genes, which disrupt crucial regulatory pathways. The speckle-type POZ protein ( SPOP ) is crucial in preventing tumor growth and is commonly altered in sporadic prostate cancers. Approximately 10 % of prostate cancers exhibit mutations in SPOP , making it the most prevalent type of non-synonymous mutation in primary prostate cancer. By utilizing various bioinformatics tools, we have identified the most harmful missense SNPs that could significantly impact the structure and function of SPOP . We employed SWISS MODEL for predicting the protein structures, and for structural analysis, we utilized the HOPE server. The molecular dynamics simulation was performed by GROMACS which revealed the notable structural stabilization and compactness the SPOP protein. MM-PBSA binding-energy analysis performed on 100 ns trajectories revealed a mean ΔG bind of -14.21± 3.02 kcal mol -1 , conforming the stable and energetically favorable interaction between Diosgenin an SPOP. Residue-level decomposition identified ASN62, ASP63, LYS64 and SER295 as key hotspots, reinforcing Diosgenin’s potential as a lead molecule for SPOP-associated prostate-cancer therapy. Protein-ligand docking was also conducted to study the interaction between the chosen ligand and the SPOP protein. In our study, we found 16 missense SNPs in the coding region of the SPOP gene. 3 SNPs (F102C, R221G, and L293H) were found to be particularly detrimental. This investigation into the study of damaging nsSNPs has the potential to be highly valuable in precision medicine, particularly when examining diseases related to SPOP .