Discovery of DNA Topoisomerase I Inhibitors with Low-Cytotoxicity Based on Virtual Screening from Natural Products

Abstract

Currently, DNA topoisomerase I (Topo I) inhibitors constitute a family of antitumor agents with demonstrated clinical effects on human malignancies. However, the clinical uses of these agents have been greatly limited due to their severe toxic effects. Therefore, it is urgent to find and develop novel low toxic Topo I inhibitors. In recent years, during our ongoing research on natural antitumor products, a collection of low cytotoxic or non-cytotoxic compounds with various structures were identified from marine invertebrates, plants, and their symbiotic microorganisms. In the present study, new Topo I inhibitors were discovered from low cytotoxic and non-cytotoxic natural products by virtual screening with docking simulations in combination with bioassay test. In total, eight potent Topo I inhibitors were found from 138 low cytotoxic or non-cytotoxic compounds from coral-derived fungi and plants. All of these Topo I inhibitors demonstrated activities against Topo I-mediated relaxation of supercoiled DNA at the concentrations of 5–100 µM. Notably, the flavonoids showed higher Topo I inhibitory activities than other compounds. These newly discovered Topo I inhibitors exhibited structurally diverse and could be considered as a good starting point for the development of new antitumor lead compounds.

Phytochemical Composition, Hepatoprotective, and Antioxidant Activities of Phyllodium pulchellum (L.) Desv

“…In addition, in our previous study, flavonoids 1 – 3 , 5 , 7 , and 9 showed DNA topoisomerase I (Topo I) inhibitory activity at a concentration of 100 μM. Particularly flavonoids 1 and 2 still exhibited potent inhibitory activity, even at 5 μM [ 47 ]. In general, the flavonoids showed significant biological activities, which should be important pharmacodynamic ingredients of P. pulchellum .…”

Natural Compounds as Therapeutic Agents: The Case of Human Topoisomerase IB

“…In normal cell lines, EGCG does not have any cytotoxic effect, as tested by a viability assay [ 60 ]. EGCG has a complex mechanism of action, and it has several targets, such as nuclear factor kappa light-chain enhancer of activated B cells (NF-kB) [ 61 ], vascular endothelial growth factor (VEGF) [ 62 ] and hTopIB [ 51 ]. A significant inhibition of hTopoIB activity but not hTopII was observed through a relaxation assay [ 51 ].…”

Computational Methodologies in the Exploration of Marine Natural Product Leads

“…Molecular docking has been the major SB methodology to predict affinities to macromolecular targets, to interpret binding modes, and to assist in the design of drug leads. Several recent publications illustrate the application of the method to MNPs [ 127 , 128 , 129 , 138 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 ], and some representative examples are here described.…”

“…A collection of 138 structures from low-cytotoxic or non-cytotoxic coral-derived fungi and plants were docked to the central catalytic domain of the Topo I–DNA complex and the 27 molecules with the most favourable predicted interactions were evaluated in vitro. Among these, four compounds showed activity at 25 μM and two compounds were active at 5 μM [ 155 ].…”