SubGDiff: A Subgraph Diffusion Model to Improve Molecular Representation Learning
Abstract
Molecular representation learning has shown great success in advancing AI-based drug discovery. The core of many recent works is based on the fact that the 3D geometric structure of molecules provides essential information about their physical and chemical characteristics. Recently, denoising diffusion probabilistic models have achieved impressive performance in 3D molecular representation learning. However, most existing molecular diffusion models treat each atom as an independent entity, overlooking the dependency among atoms within the molecular substructures. This paper introduces a novel approach that enhances molecular representation learning by incorporating substructural information within the diffusion process. We propose a novel diffusion model termed SubGDiff for involving the molecular subgraph information in diffusion. Specifically, SubGDiff adopts three vital techniques: i) subgraph prediction, ii) expectation state, and iii) k-step same subgraph diffusion, to enhance the perception of molecular substructure in the denoising network. Experimentally, extensive downstream tasks demonstrate the superior performance of our approach. The code is available at https://github.com/youjibiying/SubGDiff.
Benchmark Results
Tested on 7 datasets 18 baseline values reported too low
Tables show presented results in global context (best 3 papers + GCN + MLP).
MoleculeNet
| # | Model | ROC-AUC ↑ | Paper |
|---|---|---|---|
| 1 | HIMP | 0.8740
±0.0050 | |
| 2 | GINE w/ VN | 0.8720
±0.0030 | |
| 3 | NaiveGINe+ K=3 w/ VN | 0.8700
±0.0040 | |
| 14 | GCN | 0.8400
±0.0040 | |
| 46 | ContextPred | 0.8060
±0.0120 best reported | best at pub: KPGT: Knowledge-Guided Pre-training of Graph Transformer for Molecular Property Prediction (KDD 2022) |
| 48 | 3D Infomax | 0.8050
±0.0320 best reported | best at pub: KPGT: Knowledge-Guided Pre-training of Graph Transformer for Molecular Property Prediction (KDD 2022) Difference within reported uncertainty; not counted as underperformance. |
| 61 | GraphMVP | 0.7990
±0.0180 best reported | best at pub: KPGT: Knowledge-Guided Pre-training of Graph Transformer for Molecular Property Prediction (KDD 2022) |
| 67 | MolCLR | 0.7980
±0.0070 best reported | |
| 81 | InfoGraph | 0.7930 best reported | best at pub: GeomGCL: Geometric Graph Contrastive Learning for Molecular Property Prediction (AAAI 2021) |
| 145 | SubGDiff | 0.7720
±0.0039 | This paper |
| 153 | MoleculeSDE (VP) | 0.7700
±0.0012 | This paper |
| 214 | random init | 0.7530
±0.0022 | This paper |
| 229 | AttrMask | 0.7510
±0.0090 best reported | best at pub: Motif-aware Attribute Masking for Molecular Graph Pre-training (2023) Difference within reported uncertainty; not counted as underperformance. |
| # | Model | ROC-AUC ↑ | Paper |
|---|---|---|---|
| 1 | ProtoMol | 0.9140
±0.0030 | |
| 2 | MMSG | 0.9080
±0.0050 | |
| 3 | MemGNN | 0.9070 | |
| 9 | MolCLR | 0.8900
±0.0030 best reported | |
| 43 | GIN | 0.8646
±0.0081 | |
| 129 | SubGDiff | 0.8210
±0.0096 | This paper |
| 142 | MoleculeSDE (VP) | 0.8140
±0.0066 | This paper |
| 149 | GraphMVP | 0.8120
±0.0090 best reported | best at pub: Unified 2D and 3D Pre-Training of Molecular Representations (KDD 2022) best today: Invariant-Based Diagnostics for Graph Benchmarks (2026) Difference within reported uncertainty; not counted as underperformance. |
| 183 | 3D Infomax | 0.7970
±0.0154 | This paper |
| 182 | AttrMask | 0.7970
±0.0033 | This paper |
| 186 | ContextPred | 0.7960
±0.0120 best reported | best at pub: Graph Self-Contrast Representation Learning (2023) best today: Dual-perspective Cross Contrastive Learning in Graph Transformers (2024) |
| 204 | InfoGraph | 0.7890
±0.0110 best reported | best at pub: Omni-Granular Ego-Semantic Propagation for Self-Supervised Graph Representation Learning (ICML 2022) Difference within reported uncertainty; not counted as underperformance. |
| 234 | random init | 0.7670
±0.0251 | This paper |
| # | Model | ROC-AUC ↑ | Paper |
|---|---|---|---|
| 1 | MAGPrompt+ | 0.9432
±0.0238 | |
| 2 | CamS-LLaMA | 0.9420 | |
| 3 | SE(3)-I MPPH | 0.9400
±0.0210 | |
| 34 | GIN | 0.8875
±0.0049 | |
| 41 | 3D Infomax | 0.8770
±0.0140 best reported | best at pub: KPGT: Knowledge-Guided Pre-training of Graph Transformer for Molecular Property Prediction (KDD 2022) |
| 40 | ContextPred | 0.8770
±0.0260 best reported | best at pub: KPGT: Knowledge-Guided Pre-training of Graph Transformer for Molecular Property Prediction (KDD 2022) |
| 49 | GraphMVP | 0.8600
±0.0340 best reported | best at pub: KPGT: Knowledge-Guided Pre-training of Graph Transformer for Molecular Property Prediction (KDD 2022) |
| 78 | MolCLR | 0.7360
±0.0050 best reported | |
| 142 | SubGDiff | 0.7020
±0.0223 | This paper |
| 141 | AttrMask | 0.7020
±0.0050 best reported | best at pub: 16 Pre-training Molecular Graph Representation with 3D Geometry (ICLR 2021) best today: Graph Generative Pre-trained Transformer (ICML 2025) |
| 145 | MoleculeSDE (VP) | 0.7010
±0.0135 | This paper |
| 173 | InfoGraph | 0.6920
±0.0080 best reported | best at pub: 16 Pre-training Molecular Graph Representation with 3D Geometry (ICLR 2021) best today: Graph Generative Pre-trained Transformer (ICML 2025) |
| 200 | random init | 0.6810
±0.0059 | This paper |
| # | Model | ROC-AUC ↑ | Paper |
|---|---|---|---|
| 1 | SE(3)-I MPPH | 0.9930
±0.0040 | |
| 2 | KA-GCN | 0.9920
±0.0050 | |
| 3 | KA-GAT | 0.9910
±0.0050 | |
| 12 | MolCLR | 0.9320
±0.0170 best reported | |
| 19 | GCN | 0.9130
±0.0170 | |
| 35 | SubGDiff | 0.8820
±0.0157 | This paper |
| 40 | AttrMask | 0.8770
±0.0119 | This paper |
| 49 | GraphMVP | 0.8650
±0.0170 | This paper |
| 63 | random init | 0.8370
±0.0293 | This paper |
| 65 | MoleculeSDE (VP) | 0.8260
±0.0364 | This paper |
| 89 | 3D Infomax | 0.7990
±0.0349 | This paper |
| 106 | InfoGraph | 0.7810 best reported | best at pub: GeomGCL: Geometric Graph Contrastive Learning for Molecular Property Prediction (AAAI 2021) Difference within reported uncertainty; not counted as underperformance. |
| 115 | ContextPred | 0.7720
±0.0088 | This paper |
| # | Model | ROC-AUC ↑ | Paper |
|---|---|---|---|
| 1 | KA-GAT | 0.8470
±0.0020 | |
| 2 | KA-GCN | 0.8420
±0.0010 | |
| 3 | GraphKAN | 0.8370
±0.0010 | |
| 14 | MolCLR | 0.6800
±0.0110 best reported | |
| 66 | GIN | 0.6403
±0.0104 | |
| 70 | GraphMVP | 0.6390
±0.0120 best reported | best at pub: Unified 2D and 3D Pre-Training of Molecular Representations (KDD 2022) |
| 104 | SubGDiff | 0.6220
±0.0097 | This paper |
| 103 | ContextPred | 0.6220
±0.0059 | This paper |
| 134 | AttrMask | 0.6120
±0.0012 | This paper |
| 147 | MoleculeSDE (VP) | 0.6080
±0.0104 | This paper |
| 155 | 3D Infomax | 0.6060
±0.0078 | This paper |
| 162 | InfoGraph | 0.6054
±0.0090 best reported | best at pub: Community-Invariant Graph Contrastive Learning (ICML 2024) Difference within reported uncertainty; not counted as underperformance. |
| 224 | random init | 0.5700
±0.0133 | This paper |
| # | Model | ROC-AUC ↑ | Paper |
|---|---|---|---|
| 1 | GeomGCL | 0.7630 | |
| 2 | LiGhT DeepGPT | 0.7570
±0.0110 | |
| 3 | CoMPT | 0.7550 | |
| 14 | GCN | 0.7350
±0.0020 | |
| 25 | 3D Infomax | 0.7160
±0.0130 best reported | best at pub: KPGT: Knowledge-Guided Pre-training of Graph Transformer for Molecular Property Prediction (KDD 2022) |
| 28 | ContextPred | 0.7140
±0.0180 best reported | best at pub: KPGT: Knowledge-Guided Pre-training of Graph Transformer for Molecular Property Prediction (KDD 2022) |
| 35 | InfoGraph | 0.7050 best reported | best at pub: GeomGCL: Geometric Graph Contrastive Learning for Molecular Property Prediction (AAAI 2021) |
| 50 | GraphMVP | 0.6890
±0.0100 best reported | best at pub: KPGT: Knowledge-Guided Pre-training of Graph Transformer for Molecular Property Prediction (KDD 2022) |
| 107 | SubGDiff | 0.6500
±0.0048 | This paper |
| 112 | MoleculeSDE (VE) | 0.6470
±0.0006 | This paper |
| 150 | AttrMask | 0.6330
±0.0060 best reported | best at pub: Motif-aware Attribute Masking for Molecular Graph Pre-training (2023) Difference within reported uncertainty; not counted as underperformance. |
| 166 | MolCLR | 0.6290
±0.0038 | This paper |
| 183 | random init | 0.6210
±0.0019 | This paper |
Quantum Chemistry
| # | Model | MAE ↓ | Paper |
|---|---|---|---|
| 1 | QHNet | 0.0000 | |
| 2 | QHNetV2 | 0.0000 | |
| 3 | PhiSNet | 0.0000 | |
| 101 | SubGDiff | 0.2520 | This paper |
| 108 | random init | 0.3800 | This paper |
