AILDE Computer-Aided Discovery of Novel Ibuprofen–Coumarin Antitumor Lead Compounds Targeting Cyclooxygenase-2

Starting from three ibuprofen-coumarin hit compounds, we designed 18 derivative compounds targeting cyclooxygenase-2 (COX-2) by introducing different substituents onto them by using the computational auto in silico ligand directing evolution (AILDE) method. After synthesizing and testing the activity, we found that 6 representative compounds have micromolar enzyme inhibitory activity against COX-2. Additionally, 16 compounds have shown certain inhibitory activity in cervical cancer cells. Among these compounds, <b>6c</b> (IC₅₀ = 0.606 μM, HeLa) and <b>7g</b> (IC₅₀ = 0.783 μM, HeLa) have exhibited excellent activity, which is approximately 10 times better than the commercial drug gefitinib. According to molecular simulation results, the halogen atoms of <b>6c</b> and <b>7g</b> on the coumarin ring can form halogen bonds with COX-2, which significantly improves their activity compared to their hit compounds <b>6a</b> and <b>7a</b>. However, the key interactions were lost in binding with COX-1. The calculation results revealed that the two compounds are selective COX-2 inhibitors, with potential selectivity indexes of 6-fold and 5-fold, respectively. The cell-based activity of compounds <b>6c</b> and <b>7g</b> toward HEK293 cells demonstrates that our compounds possess an acceptable safety toward normal cells. The results indicate that <b>6c</b> and <b>7g</b> can serve as potential lead compounds for further lucubrate.