Virtual high-throughput screening (VHTS), three-dimensional quantitative structure- activity and relationship (3D-QSAR) and molecular docking studies of novel phyto-inhibtors of topoisomerase II alpha

Topoisomerase II alpha catalyses and guides the unknotting of DNA by creating double transient breaks in the DNA using a conserved tyrosine as the catalytic residue. Topoisomerase II alpha has been shown to be overexpressed in numerous types of cancers and it is a target for multiple chemotherapeutic agents. Many DNA topoisomerase inhibitors have been identified from natural sources and have been reviewed in many reports as anticancer agents. In the present study, a total of 240 phytochemicals characterized from four reported anticancer plants (Anacardium occidentale, Andrographis paniculata, Cannabis sativa and Tinospora cordifolia) were obtained from literatures and screened against the binding pocket of topoisomerase II alpha. From the pool of phytochemicals only 7-o-methylcyanidin, 20-betaecdysone, Andropanoside and Palmatoside-G qualified as Phyto-compounds with good oral bioactivity when subjected to the Lipinski’s rule of five. Bioassay data containing the IC₅₀ of compounds screened against topoisomerase II alpha was used to generate a regression model using the 3D-QSAR techniques. A very viable model with R² = 0.954, adjusted R² = 0.908, Pearson R = 0.977, cross validation Q² = 0.851, Standard Error of Estimate = 0.125, F = (20.803, p < 0.05) and Durbin-Watson constant = 1.613 was obtained. The 3D-QSAR result shows that Andropanoside and 20-betaecdysone may be better inhibitors of topoisomerase II alpha catalytic site than the standard drug, Etoposide. To further confirm this, the molecular interactions of Andropanoside and 20-betaecdysone were compared to those of Etoposide using the ligand interaction interface of Maestro environment.