Design and Characterization of Neutral Linker‐Based Bis‐Intercalator via Computer Simulations: Balancing DNA Binding and Cellular Uptake

Abstract

Bis‐intercalators play a significant role in altering the DNA structure, affecting its stability, and potentially influencing various cellular processes. These compounds have gained considerable attention in medicinal chemistry and biochemistry due to their potential applications in cancer therapy, where they may interfere with DNA replication and transcription, leading to anticancer effects. Traditionally, these molecules often possess a high positive charge to enhance their affinity for the negatively charged DNA. However, due to a high positive charge, their cellular uptake is compromised, along with their enhanced potential off‐target effects. In this study, we utilized bis‐intercalator TOTO and replaced the charged linker segment (propane‐1,3‐diammonium) with a neutral peroxodisulphuric acid linker. Using molecular modeling and computer simulations (500 ns, 3 replicas), we investigated the potential of the designed molecule as a bis‐intercalator and compared the properties with the control bis‐intercalator bound to DNA. We observed that the designed bis‐intercalator exhibited improved DNA binding (as assessed through MM‐PBSA and Delphi methods) and membrane translocation permeability. With an overall reduced charge, significantly less off‐target binding of the designed molecule is also anticipated. Consequently, bis‐intercalators based on peroxodisulphuric linkers can potentially target DNA effectively, and their role in the future design of bis‐intercalators is foreseen.