Ligand-based Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies for Discovery of Potential Topoisomerase I Inhibitors

Abstract

Camptothecin (CPT), a natural product and its synthetic derivatives exert potent anticancer activity by selectively targeting DNA Topoisomerase I (Top1) enzyme. CPT and its clinically approved derivatives are used as Top1 poisons for cancer therapy suffer from many limitations related to stability and toxicity. In order to envisage structurally diverse novel chemical entity as Top1 poison with better efficacy, Ligand-based-pharmacophore model was developed using 3D QSAR pharmacophore generation (HypoGen algorithm) methodology in Discovery studio 4.1 clients. The chemical features of 29 CPT derivatives were taken as the training set. The selected pharmacophore model Hypo1 was further validated by 33 test set molecules and used as a query model for further screening of 1,087,724 drug-like molecules from ZINC databases. These molecules were subjected to several assessments such as Lipinski rule of 5, SMART filtration and activity filtration. The molecule obtained after filtration was further scrutinized by molecular docking analysis on the active site of Top1 crystal structure (PDB ID: 1T8I). Six potential inhibitory molecules have been selected by analyzing the binding interaction and Ligand-Pharmacophore mapping with the validated pharmacophore model. Toxicity assessment TOPKAT program provided three potential inhibitory ‘hit molecules’ ZINC68997780, ZINC15018994 and ZINC38550809. MD simulation of these three molecules proved that the ligand binding into the protein-DNA cleavage complex is stable and the protein-ligands conformation remains unchanged. These three hit molecules can be utilized for designing future class of potential topoisomerase I inhibitor. Keywords: Topoisomerase I, Camptothecin, Anticancer agent, Inhibitor, Pharmacophore, Virtual screening, ZINC database, Molecular dynamics, Toxicity, ADMET