# Learning to Align Molecules and Proteins: A Geometry-Aware Approach to Binding Affinity

arXiv: https://arxiv.org/abs/2509.20693 · HTML: https://mlsanity.com/paper/2509.20693/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 8 of its 19 references that are in the map.
- First posted on arXiv 25 Sep 2025.

## Builds on (most cited first, 8 of 8)

- [FiLM: Visual Reasoning with a General Conditioning Layer](https://mlsanity.com/paper/1709.07871/) (2017)
- [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)
- [Mapping the Space of Chemical Reactions Using Attention-Based Neural Networks](https://mlsanity.com/paper/2012.06051/) (2020)
- [MolTrans: Molecular Interaction Transformer for Drug Target Interaction Prediction](https://mlsanity.com/paper/2004.11424/) (2020)
- [DeepConv-DTI: Prediction of drug-target interactions via deep learning with convolution on protein sequences](https://mlsanity.com/paper/1811.02114/) (2018)
- [TxGemma: Efficient and Agentic LLMs for Therapeutics](https://mlsanity.com/paper/2504.06196/) (2025)
- [Otter-Knowledge: benchmarks of multimodal knowledge graph representation learning from different sources for drug discovery](https://mlsanity.com/paper/2306.12802/) (2023)

## Abstract (arXiv)

Accurate prediction of drug-target binding affinity can accelerate drug discovery by prioritizing promising compounds before costly wet-lab screening. While deep learning has advanced this task, most models fuse ligand and protein representations via simple concatenation and lack explicit geometric regularization, resulting in poor generalization across chemical space and time. We introduce FIRM-DTI, a lightweight framework that conditions molecular embeddings on protein embeddings through a feature-wise linear modulation (FiLM) layer and enforces metric structure with a triplet loss. An RBF regression head operating on embedding distances yields smooth, interpretable affinity predictions. Despite its modest size, FIRM-DTI achieves state-of-the-art performance on the Therapeutics Data Commons DTI-DG benchmark, as demonstrated by an extensive ablation study and out-of-domain evaluation. Our results underscore the value of conditioning and metric learning for robust drug-target affinity prediction.