Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIα

In this study, we utilized human DNA topoisomerase II alpha as a model target to outline a dynophore-based approach to catalytic inhibitor design. Based on MD simulations of a known catalytic inhibitor and the native ATP ligand analog, AMP-PNP, we derived a joint dynophore model that supplements the static structure-based-pharmacophore information with a dynamic component. Subsequently, derived pharmacophore models were employed in a virtual screening campaign of a library of natural compounds. Experimental evaluation identified flavonoid compounds with promising topoisomerase II alpha catalytic inhibition and binding studies confirmed interaction with the ATPase domain. We constructed a binding model through docking and extensively investigated it with molecular dynamics MD simulations, essential dynamics, and MM-GBSA free energy calculations, thus reconnecting the new results to the initial dynophore-based screening model. We not only demonstrate a new design strategy that incorporates a dynamic component of molecular recognition, but also highlight new derivates in the established flavonoid class of topoisomerase II inhibitors.

Automated summary

In this study, human DNA topoisomerase II alpha was utilized as a model target and a dynophore-based approach was used to design catalytic inhibitors. Through virtual screening of a library of natural compounds, flavonoid compounds with promising topoisomerase II alpha catalytic inhibition were identified. The study not only demonstrates a new design strategy that incorporates a dynamic component of molecular recognition but also highlights new derivates in the established flavonoid class of topoisomerase II inhibitors.