Design and Modeling Studies on Liriodenine derivatives as novel topoisomerase II inhibitors

Natural products have been widely used in traditional medicines and are a valuable source for new drug discovery. On the other hand, extensive molecular modeling based on crystallographic data was used to aid the design of synthetic analogues of the natural products. Therefore, in this study, we have proposed the use of molecular modeling and docking techniques to design some potential active agents based on the most effective aporphine alkaloids, liriodenine, as a novel Inhibitor of topoisomerase II. Then we have predicted possible binding conformation of the agents, which is experimentally not known, using a computational modeling method. Conformations of the designed compounds were optimized through semi-empirical method followed by PM3 calculation by using the HYPERCHEM software. Among all energy minima conformers, the global minimum was selected. Then the crystal of topoisomerase II was obtained from the Protein Data Bank (PDB) server. Finally Docking calculations were carried out using Auto-Dock program. The good interaction of the derivatives and also the Ki (inhibition constant) showed that they can be as potent topoisomerase II inhibitors and act as novel anti cancer agents. We hope this Computational study can offer some useful references in order to understand the inhibition mechanism better so that the molecular designing would be improved and modification of these series of topoisomerase II inhibitors would be more practiced. Keyword: Topoisomerase II, Natural products, Aporphine, Molecular modeling, Docking.