Charak Sonika, Srivastava Chandra Mohan, Kumar Dhruv, Mittal Lovika, Asthana Shailendra, Mehrotra Ranjana, Shandilya Manish
CSIR-National Physical Laboratory, New Delhi 110012, India; National Brain Research Centre, Manesar, Gurugram, Haryana 122051, India.
Department of Chemistry, Biochemistry and Forensic Science, Amity School of Applied Sciences, Amity University Haryana, Gurugram 122413, India.
J Photochem Photobiol B. 2025 May;266:113147. doi: 10.1016/j.jphotobiol.2025.113147. Epub 2025 Mar 8.
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 × 10 M, 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.
伊达比星（4-去甲氧基柔红霉素）是一种从佩西链霉菌中提取的柔红霉素结构类似物，由于甲氧基被氢原子取代，其抗癌疗效增强。本研究采用多方面方法，包括红外（IR）光谱、吸收光谱、圆二色性（CD）、分子对接和分子动力学（MD）模拟，研究伊达比星与RNA的结合相互作用。IR结果表明，通过光谱位移显示与鸟嘌呤和尿嘧啶有显著结合，而MD模拟揭示了与腺嘌呤的额外相互作用，突出了一种灵活的结合机制。计算得出伊达比星-RNA复合物的结合常数为K = 2.1×10 M，反映出强亲和力和稳定相互作用。热力学分析表明，负吉布斯自由能（ΔG ∼ -4.57 kcal/mol）表明在生理条件下的自发结合。进行结合自由能估计以检查复合物的结合亲和力、稳定性和相互作用，这是通过分子动力学模拟评估的。吸收光谱中观察到的增色效应进一步支持了伊达比星-RNA复合物的稳定性，表明有效的嵌入增强了碱基暴露。这种结合是由氢键、π-π堆积相互作用和静电力驱动的，这些共同稳定了复合物。值得注意的是，RNA的构象完整性在很大程度上得以保留，在IR和CD分析中关键结构特征均保持不变。相比之下，伊达比星与RNA的相互作用不同于与DNA的相互作用，后者显示出更显著的构象扰动。这些发现加深了我们对蒽环类药物功能的理解，并为开发具有更高疗效和更低副作用的新型类似物提供了有价值的见解，为未来癌症治疗中针对RNA的治疗策略提供了依据。
