Beyond Manual Curation: Augmenting Targeted Protein Degradation Databases via Agentic Literature Extraction Workflows

Proteolysis-targeting chimeras (PROTACs) induce protein degradation by recruiting a target protein to an E3 ubiquitin ligase, making degradation a joint outcome of the degrader molecule and its biological context. Although public databases contain thousands of structured molecule-target-E3 records, degradation measurements are available for only a small fraction of them. Existing supervised approaches therefore leave most recorded chemical-biological relationships unused. We introduce DegradeQuery, a context-aware prediction framework that converts these label-missing records into a pretraining signal. Its counterfactual tuple pretraining objective contrasts recorded tuples with alternatives formed by replacing the target, the E3 ligase, or both, enabling the model to learn contextual associations without assigning activity pseudo-labels. The resulting representation is then fine-tuned to predict degradation from the complete molecule-target-E3 context. On the official PROTAC-8K benchmark, DegradeQuery achieves an area under the receiver operating characteristic curve of 0.9065 and an accuracy of 0.8500, outperforming the compared methods. Controlled analyses further show that the improvement is primarily attributable to tuple-level pretraining, can be recovered using only label-missing records, and remains complementary to protein language model representations. These findings demonstrate that incompletely labeled PROTAC databases contain useful relational supervision and provide a practical route for learning context-aware degradation predictors from scarce experimental labels.

Proteolysis-targeting chimeras (PROTACs) can selectively degrade disease-causing proteins, yet predicting which targets are amenable to degradation remains a critical bottleneck: existing computational methods require the complete PROTAC molecular structure, information unavailable before synthesis. We present DegradoMap, a graph neural network that predicts PROTAC-mediated degradability from protein structure and E3 ligase identity alone -- the minimal information available at the target selection stage. The model encodes biophysical priors through lysine-weighted graph pooling with per-protein normalization, models protein-E3 compatibility via cross-attention, and integrates cellular context from the Cancer Dependency Map. On the PROTAC-8K benchmark (3,101 samples, 155 targets, 10 E3 ligases), DegradoMap achieves 0.646+-0.124 AUROC on target-unseen evaluation (best seed: 0.7449) and 0.811 AUROC on CRBN->VHL E3-unseen transfer, outperforming GNN and machine learning baselines. The model additionally recommends optimal E3 ligases with 74% Hit@3 accuracy. Two findings carry broader implications: E(3)-equivariant architectures underperform the simpler invariant design for this scalar prediction task, and ESM-2 embeddings improve peak performance only with careful regularization -- naive integration fails. DegradoMap provides pre-synthesis computational guidance for degradability assessment; its well-calibrated confidence scores (ECE = 0.029, target-unseen) enable practitioners to prioritize high-confidence predictions for experimental follow-up. However, the high seed variance (std = 0.124) and limited E3 coverage require ensembling for reliable deployment.

Machine-learning predictors of biochemical activity often exhibit large random-split-to-leave-one-target-out generalisation gaps that have been documented but not decomposed. We frame this as an evaluation-science question and use targeted protein degradation as the empirical test bed. PROTACs (proteolysis-targeting chimeras) are heterobifunctional small molecules that induce targeted protein degradation, with more than forty candidates currently in clinical trials; published predictors report AUROC of 0.85 to 0.91 under random-split cross-validation, while the leave-one-target-out (LOTO) protocol of Ribes et al. reduces performance to approximately 0.67. Random splits reward within-target interpolation, whereas LOTO measures the novel-target prediction that de-novo design depends on. We decompose this gap and identify inter-laboratory measurement variance as the dominant component, anchored by a within-target cross-laboratory cascade bounding the inter-laboratory contribution at 0.124 AUROC, well above the 0.05 contribution from binarisation-threshold choice. Across eight published architectures and ESM-2 protein language models up to 3B parameters, LOTO AUROC plateaus near 0.67, with a comparable plateau under SMILES-level deduplication; a 21-dimensional 2000-trial hyperparameter optimisation cannot break this ceiling, and the rank-1 single-seed configuration regresses by 0.161 AUROC under multi-seed validation, matching a closed-form selection-bias prediction (Bailey and Lopez de Prado, 2014). Few-shot k=5 stratified per-target retraining combined with ADMET features lifts 65-target LOTO AUROC from 0.668 to 0.7050, and post-hoc Platt scaling recovers raw output to within the 0.05 well-calibrated threshold. We release PROTAC-Bench (10,748 measurements, 173 targets, 65 LOTO folds), the variance-decomposition framework, the per-target calibration protocol, and the evaluation code.