Beyond DNA interactions: Insights into idarubicin's binding dynamics with tRNA using spectroscopic and computational...

Idarubicin (4-demethoxydaunomycin), a structural analogue of daunomycin derived from Streptomyces peucetius, exhibits enhanced anticancer efficacy due to the substitution of a methoxy group with a hydrogen atom. This study investigates the binding interactions of idarubicin with RNA using a multifaceted approach, including infrared (IR) spectroscopy, absorption spectroscopy, circular dichroism (CD), molecular docking, and molecular dynamics (MD) simulations. The IR results demonstrate significant binding to guanine and uracil, indicated by spectral shifts, while MD simulations reveal additional interactions with adenine, highlighting a flexible binding mechanism. The binding constant of the idarubicin-RNA complex was calculated to be K = 2.1 × 10³ M^-1, reflecting a strong affinity and stable interaction. Thermodynamic analysis shows that the negative Gibbs free energy (ΔG ∼ -4.57 kcal/mol) signifies spontaneous binding under physiological conditions. The binding free energy estimation was carried out to check the binding affinity, stability and interactions of the complex which was assessed through molecular dynamics simulations. The stability of the idarubicin-RNA complex is further supported by a hyperchromic effect observed in absorption spectroscopy, suggesting effective intercalation that enhances base exposure. The binding is driven by hydrogen bonding, π-π stacking interactions, and electrostatic forces, which collectively stabilize the complex. Notably, the conformational integrity of RNA is largely preserved, with key structural features remaining unchanged in both IR and CD analyses. Comparatively, idarubicin's interactions with RNA differ from those with DNA, where the latter shows more substantial conformational perturbations. These findings enhance our understanding of anthracycline functionality and provide valuable insights for developing novel analogues with improved efficacy and reduced side effects, informing future therapeutic strategies targeting RNA in cancer treatment.