Beyond the catalytic site: Voxilaprevir and Pasireotide as repurposed therapeutics for conformational inhibition of ADAR1.

Adenosine deaminase acting on RNA 1 (ADAR1) is a central regulator of tumor immune evasion, suppressing innate immune sensing of endogenous double-stranded RNA (dsRNA) through adenosine-to-inosine (A-to-I) editing. Despite its therapeutic potential, inhibitor development remains constrained, predominantly targeting the canonical Zn2+-binding pocket or the Zα domain. Here, we present a structure-based drug repurposing strategy exploiting the RNA-free, closed-state conformation of ADAR1 to discover non-canonical inhibitors driven by conformational modulation. Through virtual screening of an FDA-approved library, coupled with multi-stage docking and extended molecular dynamics simulations, we identified Voxilaprevir and Pasireotide as robust candidate ligands. Both compounds demonstrated stable binding trajectories, anchored by persistent interactions at the catalytic periphery without deep active-site insertion. Voxilaprevir rapidly achieves a stable pose that sterically occludes the catalytic cavity, whereas Pasireotide exhibits pronounced adaptive plasticity before locking into a broad interaction network. Thermodynamic profiling confirms that binding is overwhelmingly driven by van der Waals forces, a hallmark of engaging flexible, solvent-exposed interfaces. Given their established intersections with cancer biology, particularly Pasireotide's intrinsic antiproliferative activity, these findings champion a novel mechanism of ADAR1 inhibition via conformational trapping and steric occlusion. While experimental validation is required, these findings suggest an expanded and previously underexplored chemical space for ADAR1 modulation and support drug repositioning as a promising strategy for next-generation cancer immunotherapy.