ISSN 1017-2548(Print)
ISSN 2234-8530(Online)
Volume 49, Number 5
JKCSEZ 49(5)
October 20, 2005 

We present binding modes of newly synthesized benz[f]indole-4,9-dione analogs with topoisomerase I (TOP1)-DNA complex. The compounds were tested for cytotoxicity and TOP1 inhibitory activity in our previous study. Camptothecin (CPT) and each of the 15 analogs were docked into the X-ray crystal structure of human TOP1-DNA binary complex to develop the ternary complex of TOP1-DNA-ligand using FlexiDock. The results demonstrated that two compounds with N₁-attached halogens intercalated exactly between the -1 and +1 DNA bases, deeply toward the cleavage site and were stabilized by three H-bonds each and an array of hydrophobic interactions with both the enzyme and the DNA. The most potent inhibitory activities they showed in the test agree well with the proper docking results. Six compounds which did not intercalate and formed no H-bond showed no or very low inhibitory activities. Seven compounds that intercalated between the bases with one to four H-bonds but not deeply enough toward the cleavage site showed intermediate activities. The structure-activity relationship was consistent with the experimental data. The ternary complex presented potential binding mode of each compound and thus could provide a rational basis for novel inhibitor design to develop potent anticancer drugs targeting TOP1.