# Phi-Former: A Pairwise Hierarchical Approach for Compound-Protein Interactions Prediction

arXiv: https://arxiv.org/abs/2602.05479 · HTML: https://mlsanity.com/paper/2602.05479/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 9 of its 34 references that are in the map.
- First posted on arXiv 5 Feb 2026.

## Builds on (most cited first, 9 of 9)

- [Semi-Supervised Classification with Graph Convolutional Networks](https://mlsanity.com/paper/1609.02907/) (2016)
- [Inductive Representation Learning on Large Graphs](https://mlsanity.com/paper/1706.02216/) (2017)
- [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)
- [EquiBind: Geometric Deep Learning for Drug Binding Structure Prediction](https://mlsanity.com/paper/2202.05146/) (2022)
- [One Transformer Can Understand Both 2D & 3D Molecular Data](https://mlsanity.com/paper/2210.01765/) (2022)
- [Structure-aware Interactive Graph Neural Networks for the Prediction of Protein-Ligand Binding Affinity](https://mlsanity.com/paper/2107.10670/) (2021)
- [Molecular Representation Learning via Heterogeneous Motif Graph Neural Networks](https://mlsanity.com/paper/2202.00529/) (2022)
- [SS-GNN: A Simple-Structured Graph Neural Network for Affinity Prediction](https://mlsanity.com/paper/2206.07015/) (2022)

## Abstract (arXiv)

Drug discovery remains time-consuming, labor-intensive, and expensive, often requiring years and substantial investment per drug candidate. Predicting compound-protein interactions (CPIs) is a critical component in this process, enabling the identification of molecular interactions between drug candidates and target proteins. Recent deep learning methods have successfully modeled CPIs at the atomic level, achieving improved efficiency and accuracy over traditional energy-based approaches. However, these models do not always align with chemical realities, as molecular fragments (motifs or functional groups) typically serve as the primary units of biological recognition and binding. In this paper, we propose Phi-former, a pairwise hierarchical interaction representation learning method that addresses this gap by incorporating the biological role of motifs in CPIs. Phi-former represents compounds and proteins hierarchically and employs a pairwise pre-training framework to model interactions systematically across atom-atom, motif-motif, and atom-motif levels, reflecting how biological systems recognize molecular partners. We design intra-level and inter-level learning pipelines that make different interaction levels mutually beneficial. Experimental results demonstrate that Phi-former achieves superior performance on CPI-related tasks. A case study shows that our method accurately identifies specific atoms or motifs activated in CPIs, providing interpretable model explanations. These insights may guide rational drug design and support precision medicine applications.