Insights on the binding and selectivity of surfen towards different DNA topologies

Surfen is widely recognized for its anticoagulant properties in clinical applications. Recent interest, however, has shifted toward exploring its potential interactions with DNA, which may pave the way for novel therapeutic strategies, particularly in areas where regulation of DNA structure and function is critical. In view of this, we have investigated surfen's interaction with various DNA topologies, namely double stranded DNA (dsDNA), antiparallel G-quadruplex (AP GQ-DNA), hybrid G-quadruplex (HB GQ-DNA) and triplex DNA (tDNA) through a combination of experimental approaches and molecular dynamics simulations. This integrated strategy provided a comprehensive understanding of surfen's binding preferences and its structural impact on different DNA topologies. Experimental data, including conformational and binding analysis, demonstrated that surfen stabilizes dsDNA more effectively than G-quadruplex and triplex forms through the groove binding mode. Fluorescence intensity, lifetime changes, and competitive drug displacement data support the minor groove binding mode for surfen with dsDNA. These findings are supported by molecular dynamics (MD) simulations, which revealed a higher number of stable hydrogen bonds and a notable decrease in the radius of gyration (<i>R</i>_g) for dsDNA upon surfen binding, indicating compaction and structural stabilization. In contrast, surfen binding to AP and HB G-quadruplexes led to increased RMSD values and fluctuating hydrogen bond profiles, suggesting more transient and less stable interactions. Notably, HB GQ-DNA exhibited a dynamic structural transition during the simulation, implying a possible conversion to a more stable anti-parallel form upon extended drug interaction, also supported by circular dichroism (CD) study. The docking study emphasizes the critical role of DNA groove architecture, surfen shape, and functional group positioning in molecular recognition. These combined results highlight surfen's structural preference for duplex DNA and its potential to selectively stabilize specific DNA conformations, with implications for therapeutic targeting of genomic regions with distinct structural motifs.