Unveiling therapeutic potential: In Silico discovery of prognostic markers and potential inhibitors for TGFßR1 in pancreatic cancer.

Pancreatic cancer remains one of the lethal malignancies. Characterised by low survival rates, resistance to conventional chemotherapy and a lack of early detection markers. Differentially expressed genes AHNAK2, TSC2, LAMC2, C3orf52 and IGFBP3 were identified as significant prognostic markers based on their expression pattern and poor patient survival. Mutational analysis of the TCGA-PAAD data showed a 20.93 % mutation frequency in SMAD4, which is a key regulator of TGF-ß signaling. Consequently, TGFßR1 was selected as a potential therapeutic target. A structure-based virtual screening approach was employed on a small molecule library of 101,324 compounds. Based on pharmacokinetic properties, binding affinity, non-bonded interactions, and stereochemical considerations, Compound 6, Compound 7, and Compound 8 were shortlisted. To further understand the dynamic behaviour and binding mechanism of TGFßR1 of these shortlisted compounds, molecular dynamics simulations were performed. Analysis revealed critical residues ASP351, LYS232, LYS337, and LYS213, essential for receptor stability. Additionally, umbrella sampling revealed the unbinding mechanism. These hits exhibited lower free energies (ΔG) as compared to the benchmark inhibitors, Galunisertib and Vactosertib. The results offer valuable insights into the binding mechanism of protein TGFßR1 and its role in the disease, suggesting that targeting the TGF-ß signaling pathway may represent a promising therapeutic strategy.