Computational Analysis of a Next-Generation Platinum-Based Chemotherapies that Induce DNA Double-Strand Breaks.

Platinum-based chemotherapeutic agents, such as cisplatin (Cis-Pt(II)), are widely used in cancer treatment but are limited by toxicity, DNA repair by cancer cells, and drug resistance. To address these limitations, we designed and synthesized in our laboratories a novel platinum-based compound, Aurkine16. In our previous studies, Aurkine16 demonstrated outstanding therapeutic efficacy, selectively inducing double-strand DNA breaks in both naïve and cisplatin-resistant cancer cells, without detectable toxic side effects at clinically relevant doses. In the present work, we report a computational analysis of Aurkine16, which reveals its unique activation pathway and its capacity to form stable [Aurki-GGG]3+ complexes. Unlike Cis-Pt(II), which induces single-strand DNA breaks, Aurkine16 simultaneously targets multiple nucleic bases, causing double-strand breaks and significant DNA disruption. Additionally, molecular dynamics simulations suggest that Aurkine16 is likely to exhibit specificity for cancer cells, avoiding off-target interactions within the nucleosome core. This selectivity, attributed to the steric hindrance from histone tails, underscores its potential for effectively targeting chromatin-accessible cancer cells. These computational findings position Aurkine16 as a promising alternative to platinum-based drugs, particularly for CisPt-resistant cancers.