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. 2002 Feb 1;30(3):794–802. doi: 10.1093/nar/30.3.794

Figure 9.

Figure 9

(A) Model of the inhibitor CPT bound to the covalent complex of putative LdTOP1 and DNA. In this model, CPT (space-filling representation with nitrogen atoms in blue, oxygen in red, carbon in green and the A, B and E rings of the molecule indicated) stacks in the DNA duplex in place of the guanine base at the +1 Gua position of the scissile strand, which has been flipped out of the duplex. CPT makes a stacking interaction with this +1 base bringing the C7 atom of the drug in close proximity to the N3 atom of +1 Gua. Two of the CPT-resistant mutations reported in human, represented by Arg190 and Asp353 in the parasite protein model, were found to interact in an analogous manner with the required lactone and 20(S)-hydroxyl moieties of CPT. (B) A schematic representation of the key hydrogen bonds and ring-stacking interactions made between the LdTOP1–DNA covalent complex model and CPT in the proposed CPT-binding mode is shown.