DNA topoisomerase 1 (Top1) is a prime target of chemotherapy agents and a crucial enzyme that maintains DNA topology, during transcription, replication, repair, and recombination by relaxing DNA torsional strain through reversible DNA single-strand breaks process. Top1 is a selective target of camptothecin (CPT), a natural alkaloid compound and an important class of anti-cancer drugs, that reversibly bind the covalent DNA–Top1 complex, slowing down the religation of the cleaved DNA strand, thus inducing cell death. However, the use of CPTs was hampered by several drawbacks. In the present study, we have performed a receptor-ligand molecular docking analysis of a set of 738 camptothecin-like molecules in order to identify new potential derivative structures of camptothecin, a more potent anticancer agent with better efficacy, less toxicity, and side effects. MolDock score and hydrogen bonding interactions are the parameters used for docking studies. The inhibition phenomenon is mainly governed by various non-covalent interactions, including hydrogen bonds, steric interactions, and van der Waals interactions between the DNA basis and ligand. Among the top 10 ranked molecules, all the CPT similar ligands were found to have higher binding affinity in comparison with the CPT of the human DNA–Top1. The first ranked molecule (21882279) showed the highest docking score value (− 229.993 kcal/mol) which it binds to the cavity by Arg364 residue. These results suggest that similar ligands may serve as a leading compound for the development of anticancer agents. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.