# Chemical and geometric representation fidelity improves drug--target affinity prediction

arXiv: https://arxiv.org/abs/2609.13230 · HTML: https://mlsanity.com/paper/2609.13230/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 7 of its 41 references that are in the map.
- First posted on arXiv 2 Sep 2026.

## Builds on (most cited first, 7 of 7)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [Self-Attention with Relative Position Representations](https://mlsanity.com/paper/1803.02155/) (2018)
- [DeepDTA: Deep Drug-Target Binding Affinity Prediction](https://mlsanity.com/paper/1801.10193/) (2018)
- [WideDTA: prediction of drug-target binding affinity](https://mlsanity.com/paper/1902.04166/) (2019)
- [GEFA: Early Fusion Approach in Drug-Target Affinity Prediction](https://mlsanity.com/paper/2009.12146/) (2020)
- [Graph Neural Networks in Modern AI-aided Drug Discovery](https://mlsanity.com/paper/2506.06915/) (2025)
- [SSM-DTA: Breaking the Barriers of Data Scarcity in Drug-Target Affinity Prediction](https://mlsanity.com/paper/2206.09818/) (2022)

## Abstract (arXiv)

Predicting drug--target binding affinity (DTA) requires models to distinguish subtle chemical and structural determinants underlying molecular recognition. Although recent approaches increasingly incorporate richer drug and protein information, such information may be compressed, homogenized or discretized during representation construction, causing affinity-relevant distinctions to be lost before interaction modelling. We hypothesized that this representation-stage information loss constitutes an upstream bottleneck that cannot be reliably overcome by increasingly complex interaction predictors. To test this hypothesis, we developed ReGeoDTA, a representation-preserving framework that maintains affinity-relevant chemical heterogeneity in molecular representations and continuous geometric relationships in protein structures. Across three benchmark datasets, ReGeoDTA consistently improved affinity prediction, and the proposed representation-preserving strategies retained their benefits across diverse DTA architectures. Controlled representation degradation progressively reduced predictive performance, whereas increasing downstream predictor complexity failed to recover information lost during representation construction. These findings identify representation fidelity as an upstream design principle for accurate and generalizable drug--target affinity prediction, with potential implications for computational compound prioritization.