Structural stability-guided scaffold hopping and computational modeling of tankyrase inhibitors targeting colorectal cancer

Colorectal cancer is one of the leading causes of cancer-related deaths worldwide, mainly due to aberrant Wnt/β-catenin signaling resulting from APC mutations. Tankyrase is a key regulator of this pathway and plays a crucial role in stabilizing AXIN, a negative regulator of β-catenin, and hence an attractive therapeutic target. The present study describes a comprehensive computational approach to discovering novel tankyrase inhibitors for CRC therapy. The reference (RK-582) for ligand-based screening and comparative analysis was taken from the crystal structure of tankyrase. A similarity search in the PubChem, applying an 80% cutoff, yielded 533 structurally similar compounds. These compounds were subjected to virtual screening using a drug-likeness filter. The top-ranking binding poses of three selected compounds (PubChem CIDs: 138594346, 138594730, and 138594428) were selected for DFT calculation and re-docking. DFT calculations revealed that compound 138594428 had the largest HOMO-LUMO gap (4.979 eV), indicating high electronic stability, while 138594346 exhibited a strong balance of stability and reactivity (4.473 eV). The MD simulations were conducted on all ns protein-ligand complexes for 500 ns, exploring their stability. MD simulations confirmed the conformational stability of these compounds, with 138594346 showing the lowest RMSD and RMSF fluctuations. Additionally, a machine learning model trained on 236 known Tankyrase inhibitors accurately predicted pIC₅₀ values, with compound 138594346 (pIC₅₀ = 7.70) closely matching the reference inhibitor (pIC₅₀ = 7.71), and 138594428 also exhibiting strong predicted activity (pIC₅₀ = 7.41). Collectively, these results highlight 138594346 and 138594428 as promising candidates for further experimental validation in the development of targeted CRC therapeutics.