Computational targeting of APE1-miRNA interactions in Cancer: Prioritization of candidate modulators.

Abstract

Tumor development and resistance to therapy are influenced by adaptive transcriptional and post-transcriptional processes, including dysregulated miRNA biogenesis. APE1 participates in canonical DNA-repair and redox functions as well as non-canonical RNA-associated processes, making selective investigation of its RNA interactions of potential interest. We used a two-phase virtual-screening workflow, followed by molecular dynamics simulations (MD simulations), model-dependent MM/PBSA estimates, free-energy landscape projections, and preliminary REMSA evaluation. Docking against a single refined full-length APE1 model identified candidate poses near the modeled N-terminal/RNA-related region and at C-terminal/AP-site-associated locations; these assignments are conditional on the structural models and do not establish binding sites. Analyses of predicted ligand orientations, residue-level contacts, and trajectory-derived descriptors provided an evidence for candidate prioritization. ZINC04237094 and ZINC15675770 were retained from the APE1-only screening phase, whereas ZINC49155170 and ZINC04258889 were prioritized from the APE1-hsa-miR-1246 phase using stepwise, sequential computational criteria. One purchasable representative from each phase was selected for preliminary REMSA evaluation, with availability and acquisition cost considered separately from computational performance. Across two replicate concentration series, ZINC15675770 and ZINC04258889 showed negative concentration-associated trends in the normalized APE1-hsa-miR-1246 complex signal. These preliminary results do not establish direct compound binding, interface disruption, binding-site location, functional selectivity, or preservation of APE1 DNA-repair and redox functions. Collectively, this study provides a computational prioritization framework and preliminary evidence supporting further investigation of candidate modulators of APE1-associated miRNA interactions.