Chiang Mai Journal of Science

 Topoisomerase IIα plays a vital role in regulating DNA replication and transcription, and ensuring the successful unfolding, segregation, and condensation of chromosomes during mitosis. Because of its crucial function, it has become the target of several anticancer drugs that seek to disrupt the cell cycle of cancerous cells. In this study, we explored the potential for porphyrin-acridine hybrid compounds in inhibiting Topoisomerase IIα. We have designed porphyrin-acridine compounds with varying meso-substituents, and modeled their interactions with Topoisomerase IIα through molecular docking and molecular dynamics simulations. The porphyrin-acridine compounds interacted with the DNA at the Topoisomerase-DNA cleavage complex through intercalation and groove binding, assisted by strong hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations show that mono-H2PyP-AC and bis-H2PzP-AC formed stable complexes with their targets. Binding free energy calculations also show that electrostatic interactions formed by the cationic meso substituents contributed to the overall interaction, and that the acridine moiety significantly strengthened the bond between ligand and target.