Structural insights into fungal and human topoisomerase II with implications for in silico antifungal drug design.

Topoisomerases are essential enzymes regulating DNA supercoiling and disentanglement, critical for genomic integrity. While topoisomerase inhibitors are well-established in anticancer and antibacterial chemotherapy, their potential as antifungal agents remains underexplored or even not proofed. This study investigates structural distinctions between Saccharomyces cerevisiae topoisomerase II (ScTopoII) and human topoisomerase IIα (hTopoIIα), aiming to identify if ScTopoII can be a selective target for antifungal drug development. A comprehensive sequence analysis, extending to various fungal strains and evolutionary ancient organisms, reveals dissimilarities in the transducer and transducer linker domains of these proteins, as well as in the lysine-rich K-loop region. Molecular dynamics simulations emphasize structural differences in the K-loop, α-helix (or helix-like region), and helix supporting loop region, as well as show unique patterns in hydrophilic and hydrophobic intramolecular interactions in ScTopoII. Moreover, phylogenetic comparisons support the importance of specific regions studied. The study includes topos from different organisms, highlighting discrepancies in helix stability near the K-loop and the role of helix supporting loop region. This broad analysis provides insights into the structural basis of human and fungal enzymes presenting potential pharmacophore "hot spots" in ScTopoII which may give hope for developing selective antifungal agents.