AI screening and molecular dynamic simulation-driven identification of novel inhibitors of TGFßR1 for pancreatic cancer therapy

Pancreatic cancer, with a 5-year survival rate below 10 %, is one of the deadliest malignancies. The TGF-ß pathway plays a crucial role in this disease, making it a key target for therapeutic intervention. Clinical trials targeting TGF-β have faced challenges of toxicity and limited efficacy, highlighting the need for more potent small molecule inhibitors. We selected TGFßR1 as the drug target to inhibit TGF-ß signaling in pancreatic cancer. A multi-faceted approach was employed, commencing with AI-driven screening techniques to rapidly identify potential TGFßR1 inhibitors from vast compound libraries, including the ZINC and ChEMBL databases. AI-screened compounds were further validated through structure-based high-throughput virtual screening (HTVS) to evaluate their binding affinity to TGFßR1. In addition to this, a dedicated library of anticancer compounds (65,000 compounds) and protein kinase inhibitors (36,324 compounds) were also used for HTVS. Subsequently, pharmacokinetic profiling narrowed the selection to 40 hit compounds. Five hit compounds were chosen based on binding affinity, non-bonded interactions, stereochemistry, and pharmacokinetic profiles for molecular dynamics (MD) simulations. Trajectory analysis showed that residues HIS283, ASP351, LYS232, SER280, ILE211, and LYS213 within TGFßR1's active site are crucial for ligand binding through hydrogen bonds and hydrophobic interactions. Principal component analysis (PCA) and Dynamic cross-correlation matrix (DCCM) analysis were used to evaluate the receptor's dynamic response to the hit compounds. The simulation data revealed that compounds 1, 2, 3, 4, and 5 formed stable complexes with TGFßR1. Notably, post-MDS MM-GBSA analysis showed that compounds 4 and 5 exhibited exceptionally strong binding energies of −81.0 kcal/mol and −85.5 kcal/mol, respectively. The comprehensive computational analysis confirms compounds 4 and 5 as promising TGFßR1 hits with potential therapeutic applications in development of new treatments for pancreatic cancer.