1. Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIα.
- Author
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Janežič M, Valjavec K, Loboda KB, Herlah B, Ogris I, Kozorog M, Podobnik M, Grdadolnik SG, Wolber G, and Perdih A
- Subjects
- Antigens, Neoplasm metabolism, Antineoplastic Agents pharmacology, Binding Sites, Catalytic Domain physiology, DNA Topoisomerases, Type II genetics, DNA Topoisomerases, Type II metabolism, DNA-Binding Proteins metabolism, Humans, Molecular Docking Simulation, Structure-Activity Relationship, Topoisomerase II Inhibitors chemical synthesis, Topoisomerase II Inhibitors metabolism, Drug Design methods, Topoisomerase II Inhibitors pharmacology
- Abstract
In this study, we utilized human DNA topoisomerase IIα 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 IIα 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.
- Published
- 2021
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