Assay-Aware BindingDB: Curating Experimental Context for Binding Affinity Prediction

Abstract

Protein--ligand binding affinity prediction is fundamental to computational drug discovery, yet modern AI-driven models are limited by pervasive heterogeneity in their training data: bioactivity values are aggregated across diverse assay types and experimental conditions without accounting for protocol-level differences, introducing systematic noise. Existing harmonization approaches either discard assay-level metadata or collapse it into coarse categorical distinctions, leaving rich contextual signal unused. We address this gap with two contributions. First, we introduce Assay-Aware BindingDB, augmenting 74,425 BindingDB protein--ligand pairs across four assay types (ITC, SPR, RBA, and FPA) with structured metadata extracted from primary literature using a two-stage agentic framework that separates evidence extraction from ontology-conditioned JSON synthesis. Against domain-expert references, the framework achieves presence F1 $\geq 0.947$ and semantic content accuracy $\geq 0.913$ across all assay types. Second, we develop a context-conditioned affinity model that injects an assay-context embedding into the Boltz-2 affinity module. On a paper-level held-out split, the model reduces combined-regime MSE from $1.27$ to $1.19$ and increases Pearson correlation from $0.64$ to $0.67$, with significant gains for SPR and FPA. ITC, the only label- and immobilization-free assay considered, shows no improvement, consistent with its design removing the protocol artifacts the metadata captures. These results support the hypothesis that systematically curated assay metadata provides informative signal for affinity prediction.