AILDE Computer-Aided\nDiscovery of Novel Ibuprofen–Coumarin\nAntitumor Lead Compounds Targeting Cyclooxygenase‑2

Starting from three ibuprofen–coumarin hit compounds,\nwe\ndesigned 18 derivative compounds targeting cyclooxygenase-2 (COX-2)\nby introducing different substituents onto them by using the computational\nauto in silico ligand directing evolution (AILDE) method. After synthesizing\nand testing the activity, we found that 6 representative compounds\nhave micromolar enzyme inhibitory activity against COX-2. Additionally,\n16 compounds have shown certain inhibitory activity in cervical cancer\ncells. Among these compounds, <b>6c</b> (IC<sub>50</sub> = 0.606\nμM, HeLa) and <b>7g</b> (IC<sub>50</sub> = 0.783 μM,\nHeLa) have exhibited excellent activity, which is approximately 10\ntimes better than the commercial drug gefitinib. According to molecular\nsimulation results, the halogen atoms of <b>6c</b> and <b>7g</b> on the coumarin ring can form halogen bonds with COX-2,\nwhich significantly improves their activity compared to their hit\ncompounds <b>6a</b> and <b>7a</b>. However, the key interactions\nwere lost in binding with COX-1. The calculation results revealed\nthat the two compounds are selective COX-2 inhibitors, with potential\nselectivity indexes of 6-fold and 5-fold, respectively. The cell-based\nactivity of compounds <b>6c</b> and <b>7g</b> toward HEK293\ncells demonstrates that our compounds possess an acceptable safety\ntoward normal cells. The results indicate that <b>6c</b> and <b>7g</b> can serve as potential lead compounds for further lucubrate.