Type II DNA topoisomerases are biological molecular motors that catalyze topological changes in DNA molecules and are considered important targets for anticancer drugs. Using molecular simulations and experimental data, we developed a dynamic model of various configurations of topoisomerase IIA in its catalytic cycle. The simulations revealed that both the rotational movement of the dimer and the sliding motion within the DNA gates are inherent dynamic properties of the enzyme. Furthermore, ATP could play a crucial role in the stabilization of the T-segment, as ATP hydrolysis increased the conformational activity of the N-gate.
To overcome the limitations of current topoisomerase poisons used in chemotherapy catalytic inhibitors of human topoisomerase IIα that target the ATP binding site were developed. By utilizing molecular simulations and artificial intelligence, we optimized inhibitors from the group of 4,6-substituted-1,3,5-triazine-2(1H)-ones, where the introduced bicyclic substituents at position 6 maintained inhibitory activity and somewhat improved the physicochemical properties of the compounds. In addition, a novel approach for designing compounds was developed using dynamic pharmacophore models. To validate this method, the ATP binding site of human DNA topoisomerase IIα was examined, and new catalytic inhibitors of natural origin were identified. The derived pharmacophore model was then used to identify a class of substituted 3-(imidazol-2-yl) morpholines which selectively inhibit topoisomerase IIα and bind to its ATPase domain. These compounds also exhibit cytotoxic properties through a mechanism that is different from that of topoisomerase poisons.
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