Microscopic modes and free energies for topoisomerase I-DNA covalent complex binding with non-camptothecin inhibitors by molecular docking and dynamics simulations

Topoisomerase I (Topo1) has been identified as an attractive target for anticancer drug development due to its central role in facilitating the nuclear process of the DNA. It is essential for rational design of novel Topo1 inhibitors to reliably predict the binding structures of the Topo1 inhibitors interacting with the Topo1-DNA complex. The detailed binding structures and binding free energies for the Topo1-DNA complex interacting with typical non-camptothecin Topo1 inhibitors have been examined by performing molecular docking, molecular dynamic simulations, and binding free energy calculations. The computational results provide valuable insights into the binding modes of the inhibitors binding with the Topo1-DNA complex and the key factors affecting the binding affinity. It has been demonstrated that the π–π stacking interaction with the DNA base pairs and the hydrogen bonding with Topo1 have the pivotal contributions to the binding structures and binding free energies, although the van der Waals and electrostatic interactions also significantly contribute to the stabilization of the binding structures. The calculated binding free energies are in good agreement with the available experiment activity data. The detailed binding modes and the crucial factors affecting the binding free energies obtained from the present computational studies may provide valuable insights for future rational design of novel, more potent Topo1 inhibitors.