Generated 3D‐Common Feature Hypotheses Using the HipHop Method For Developing New Topoisomerase I Inhibitors

The continued interest in designing novel topoisomerase I (Topo I) inhibitors and the lack of adequate ligand‐based computer‐aided drug discovery efforts combined with the drawbacks of structure‐based design prompted us to explore the possibility of developing ligand‐based three‐dimensional (3D) pharmacophore(s). This approach avoids the pitfalls of structure‐based techniques because it only focuses on common features among known ligands; furthermore, the pharmacophore model can be used as 3D search queries to discover new Topo I inhibitory scaffolds. In this article, we employed the HipHop module using Discovery Studio to construct plausible binding hypotheses for clinically used Topo I inhibitors, such as camptothecin, topotecan, belotecan, and SN‐38, which is an active metabolite of irinotecan. The docked pose of topotecan was selected as a reference compound. The first hypothesis (Hypo 01) among the obtained 10 hypotheses was chosen for further analysis. Hypo 01 had six features, which were two hydrogen‐bond acceptors, one hydrogen‐bond donor, one hydrophob aromatic and one hydrophob aliphatic, and one ring aromatic. Our obtained hypothesis was checked by using some of the aromathecin derivatives which were published for their Topo I inhibitory potency. Moreover, five structures were found to be possible anti‐Topo I compounds from the DruglikeDiverse database. From this research, it can be suggested that our model could be useful for further studies in order to design new potent Topo I‐targeting antitumor drugs.