Camptothecin 유도체의 Human Topoisomerase I-DNA 복합체에 대한 Docking 연구

Docking Studies of Camptothecin Analogues into Human Topoisomerase I-DNA Complex

Human topoisomerase I (Topo I) plays a pivotal role in cell replication, transcription and repair and, therefore, is an important anti-cancer target. 20S-camptothecin (CPT) is a representative Topo I inhibitor. Compounds belonging to CPT family inhibit the religation step of Topo I-DNA by binding to the DNA cleavage site. Computational docking studies with Surflex-Dock were carried out to investigate the binding modes between Topo I-DNA binary complex structure and the ligand such as 20S-CPT and 9,10-substituted 20S-CPT analogues. The docking results demonstrated that most of the compounds with IC50 value under 0.5 μM intercalated exactly between the -1 and +1 DNA bases, deeply toward the cleavage site. The complex was stabilized by hydrogen-bonding and hydrophobic interactions with both the enzyme and the DNA. The compounds with IC50 value above 0.5 μM were poorly docked and did not intercalate. In addition, the docking results confirmed the overall correlation between the IC50 values and docking scores, indicating the possible use of the modeling for the prediction of biological activity and design of potential inhibitors.