Title: Comprehensive Benchmark for Tailored Small Molecule-Binding Aptamer Design
Primary area: datasets and benchmarks
Keywords: aptamer, small molecule, binding, prediction, benchmark

Abstract: Despite their growing role as recognition elements in diagnostics, therapeutics, and biosensing, aptamers remain underserved by computational design tools compared to antibodies and protein binders. Current pipelines are fragmented and predominantly protein-focused, leaving small-molecule aptamer discovery underexplored. A key bottleneck has been the absence of a unified benchmark dataset that would allow systematic evaluation of predictive and generative models. To address this gap, we introduce the first comprehensive benchmark for aptamer–small molecule interactions, integrating seven curated sources into 2,210 annotated pairs covering 1,430 unique aptamers (DNA and RNA) and 496 chemically diverse ligands. More than half of the entries include quantitative binding affinities, enabling not only binary classification but also regression. To demonstrate the utility of this resource, we establish baseline results across shallow and deep learning baseline models under multiple splitting protocols. Our analysis yields two key insights: (i) the coverage and diversity of aptamer sequences are sufficient to support robust modeling, ensuring that receptor-side representation is not the limiting factor; and (ii) the main challenge arises from the ligand space, where a relatively small number of molecules display high structural diversity, limiting model transferability. Because the ultimate goal is designing aptamers for previously unseen molecules, the observed limitations in ligand transferability point directly to the representation problem, reinforcing the necessity of a common benchmark to address it. By providing a standardized corpus, evaluation protocols, and reproducible baselines, our work establishes a foundation for systematic progress in aptamer–small molecule prediction.

TL;DR: We introduce a unified benchmark for aptamer–small molecule interactions, showing that aptamer sequence diversity is well covered while ligand representation remains the main challenge for predictive modeling and practical applications.