Based on the crystallographic structure of human topoisomerase I (Topo I)-DNA covalent complex, a general model for the ternary drug-DNA- Topo I complex for camptothecin (CPT) derivatives has been developed using flexible docking teclmiques and thus elucidated the mode of action of CPT compounds interacting with Topo I and DNA from the atomic level for further design of novel potent CPT derivatives. In our model, CPT intercalated between the - 1 and + 1 base pail's of the cleavage site, stabilized further by H-bonding network between Asn722, Asp533, Lys532, Lys720 of Topo I and itself. Quantitative structure- activity relationship (QSAR) studies of 20 A-ring substituted CPT derivatives indicate that there may exist 7r-7t charge transfer interaction between CPT derivatives and Topo I-DNA complex. Our model of action for CPT provides an excellent fit between CPT and the binding site and is significantly consistent with the current knowledge of experimental mutations that render CFf resistant and structure-activity relationships of CPT derivatives, etc. This model provides a rational basis for further design and synthesis of novel potent CPT antitumor drugs.

Key words: CATALYTIC ACTIVITY, ISOMERASE, ANTITUMOR DRUGS, drug design