Molecular modeling studies of the DNA-topoisomerase I ternary cleavable complex with camptothecin

J Med Chem. 1998 Jun 18;41(13):2216-26. doi: 10.1021/jm9605445.


The present studies provide a three-dimensional model for the postulated ternary cleavable complex of topoisomerase I (top1), DNA, and camptothecin (CPT). Molecular simulations were done using the AMBER force field. The results suggest that a ternary cleavable complex might be stabilized by several hydrogen bonds in the binding site. In this proposed "drug-stacking" model, CPT is pseudointercalated in the top1-linked DNA cleavage site and interacts with the protein near its catalytic tyrosine through hydrogen bonding and stacking. The structural model is consistent with the following experimental observations: (i) the N3 position of the 5' terminal purine of the cleaved DNA strand is readily alkylated by 7-chloromethyl 10,11-methylenedioxy CPT; (ii) CPT generally tolerates substituents at positions 7, 9, and 10 but is inactivated by additions at position 12; (iii) 10,11-methylenedioxy (MDO) CPT is much more potent than 10,11-dimethoxy (DMO) CPT; (iv) the lactone portion of CPT is essential for top1 inhibitory activity; (v) 20S derivatives of CPT are much more potent than the 20R analogues; (vi) a catalytic tyrosine hydroxyl in top1 covalently links to the 3' terminal base, T, of the cleaved DNA strand; and (vii) top1 mutation Asn722Ser leads to CPT resistance. A total of 18 camptothecin derivatives with different DNA cleavage potencies were docked into the hypothetical cleavable complex binding site to test and refine the model. These studies provide insight into a possible mechanism of top1 inhibition by CPT derivatives and suggest rational approaches for the design of new CPT derivatives.

MeSH terms

  • Amino Acid Substitution
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Camptothecin / analogs & derivatives
  • Camptothecin / chemistry*
  • Camptothecin / metabolism
  • Camptothecin / pharmacology
  • DNA / chemistry*
  • DNA / metabolism
  • DNA Topoisomerases, Type I / chemistry*
  • DNA Topoisomerases, Type I / genetics
  • DNA Topoisomerases, Type I / metabolism
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Hydrogen Bonding
  • Ligands
  • Models, Molecular*
  • Molecular Conformation
  • Mutation
  • Protein Conformation
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thermodynamics
  • Topoisomerase I Inhibitors


  • 7-chloromethyl-10,11-methylenedioxycamptothecin
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Ligands
  • Topoisomerase I Inhibitors
  • DNA
  • DNA Topoisomerases, Type I
  • Camptothecin