# KEPLA: A Knowledge-Enhanced Deep Learning Framework for Accurate Protein-Ligand Binding Affinity Prediction

arXiv: https://arxiv.org/abs/2506.13196 · HTML: https://mlsanity.com/paper/2506.13196/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 17 of its 68 references that are in the map.
- First posted on arXiv 16 Jun 2025.

## Builds on (most cited first, 17 of 17)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [Adam: A Method for Stochastic Optimization](https://mlsanity.com/paper/1412.6980/) (2014)
- [PyTorch: An Imperative Style, High-Performance Deep Learning Library](https://mlsanity.com/paper/1912.01703/) (2019)
- [RotatE: Knowledge Graph Embedding by Relational Rotation in Complex Space](https://mlsanity.com/paper/1902.10197/) (2019)
- [Directional Message Passing for Molecular Graphs](https://mlsanity.com/paper/2003.03123/) (2020)
- [Analyzing Learned Molecular Representations for Property Prediction](https://mlsanity.com/paper/1904.01561/) (2019)
- [Cross Attention Network for Few-shot Classification](https://mlsanity.com/paper/1910.07677/) (2019)
- [Representing Long-Range Context for Graph Neural Networks with Global Attention](https://mlsanity.com/paper/2201.08821/) (2022)
- [DeepDTA: Deep Drug-Target Binding Affinity Prediction](https://mlsanity.com/paper/1801.10193/) (2018)
- [Molecule Attention Transformer](https://mlsanity.com/paper/2002.08264/) (2020)
- [Non-Local Graph Neural Networks](https://mlsanity.com/paper/2005.14612/) (2020)
- [MolTrans: Molecular Interaction Transformer for Drug Target Interaction Prediction](https://mlsanity.com/paper/2004.11424/) (2020)
- [Structure-aware Interactive Graph Neural Networks for the Prediction of Protein-Ligand Binding Affinity](https://mlsanity.com/paper/2107.10670/) (2021)
- [Development and evaluation of a deep learning model for protein-ligand binding affinity prediction](https://mlsanity.com/paper/1712.07042/) (2017)
- [DeepConv-DTI: Prediction of drug-target interactions via deep learning with convolution on protein sequences](https://mlsanity.com/paper/1811.02114/) (2018)
- [Interpretable bilinear attention network with domain adaptation improves drug-target prediction](https://mlsanity.com/paper/2208.02194/) (2022)
- [DGL-LifeSci: An Open-Source Toolkit for Deep Learning on Graphs in Life Science](https://mlsanity.com/paper/2106.14232/) (2021)

## Abstract (arXiv)

Accurate prediction of protein-ligand binding affinity is critical for drug discovery. While recent deep learning approaches have demonstrated promising results, they often rely solely on structural features of proteins and ligands, overlooking their valuable biochemical knowledge associated with binding affinity. To address this limitation, we propose KEPLA, a novel deep learning framework that explicitly integrates prior knowledge from Gene Ontology and ligand properties to enhance prediction performance. KEPLA takes protein sequences and ligand molecular graphs as input and optimizes two complementary objectives: (1) aligning global representations with knowledge graph relations to capture domain-specific biochemical insights, and (2) leveraging cross attention between local representations to construct fine-grained joint embeddings for prediction. Experiments on two benchmark datasets across both in-domain and cross-domain scenarios demonstrate that KEPLA consistently outperforms state-of-the-art baselines. Furthermore, interpretability analyses based on knowledge graph relations and cross attention maps provide valuable insights into the underlying predictive mechanisms.