# When Does Context Help? A Systematic Study of Target-Conditional Molecular Property Prediction

arXiv: https://arxiv.org/abs/2604.06558 · HTML: https://mlsanity.com/paper/2604.06558/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 15 of its 28 references that are in the map.
- First posted on arXiv 8 Apr 2026.

## Builds on (most cited first, 15 of 15)

- [How Powerful are Graph Neural Networks?](https://mlsanity.com/paper/1810.00826/) (2018)
- [Neural Message Passing for Quantum Chemistry](https://mlsanity.com/paper/1704.01212/) (2017)
- [Axiomatic Attribution for Deep Networks](https://mlsanity.com/paper/1703.01365/) (2017)
- [FiLM: Visual Reasoning with a General Conditioning Layer](https://mlsanity.com/paper/1709.07871/) (2017)
- [HyperNetworks](https://mlsanity.com/paper/1609.09106/) (2016)
- [Strategies for Pre-training Graph Neural Networks](https://mlsanity.com/paper/1905.12265/) (2019)
- [Gated Graph Sequence Neural Networks](https://mlsanity.com/paper/1511.05493/) (2015)
- [SchNet: A continuous-filter convolutional neural network for modeling quantum interactions](https://mlsanity.com/paper/1706.08566/) (2017)
- [Directional Message Passing for Molecular Graphs](https://mlsanity.com/paper/2003.03123/) (2020)
- [ChemBERTa: Large-Scale Self-Supervised Pretraining for Molecular Property Prediction](https://mlsanity.com/paper/2010.09885/) (2020)
- [Therapeutics Data Commons: Machine Learning Datasets and Tasks for Drug Discovery and Development](https://mlsanity.com/paper/2102.09548/) (2021)
- [Molecular representation learning with language models and domain-relevant auxiliary tasks](https://mlsanity.com/paper/2011.13230/) (2020)
- [Protein-Ligand Scoring with Convolutional Neural Networks](https://mlsanity.com/paper/1612.02751/) (2016)
- [Massively Multitask Networks for Drug Discovery](https://mlsanity.com/paper/1502.02072/) (2015)
- [AtomNet: A Deep Convolutional Neural Network for Bioactivity Prediction in Structure-based Drug Discovery](https://mlsanity.com/paper/1510.02855/) (2015)

## Abstract (arXiv)

We present the first systematic study of when target context helps molecular property prediction, evaluating context conditioning across 10 diverse protein families, 4 fusion architectures, data regimes spanning 67-9,409 training compounds, and both temporal and random evaluation splits. Using NestDrug, a FiLM-based architecture that conditions molecular representations on target identity, we characterize both success and failure modes with three principal findings. First, fusion architecture dominates: FiLM outperforms concatenation by 24.2 percentage points and additive conditioning by 8.6 pp; how you incorporate context matters more than whether you include it. Second, context enables otherwise impossible predictions: on data-scarce CYP3A4 (67 training compounds), multi-task transfer achieves 0.686 AUC where per-target Random Forest collapses to 0.238. Third, context can systematically hurt: distribution mismatch causes 10.2 pp degradation on BACE1; few-shot adaptation consistently underperforms zero-shot. Beyond methodology, we expose fundamental flaws in standard benchmarking: 1-nearest-neighbor Tanimoto achieves 0.991 AUC on DUD-E without any learning, and 50% of actives leak from training data, rendering absolute performance metrics meaningless. Our temporal split evaluation (train up to 2020, test 2021-2024) achieves stable 0.843 AUC with no degradation, providing the first rigorous evidence that context-conditional molecular representations generalize to future chemical space.