# IBEX: Information-Bottleneck-EXplored Coarse-to-Fine Molecular Generation under Limited Data

arXiv: https://arxiv.org/abs/2508.10775 · HTML: https://mlsanity.com/paper/2508.10775/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Builds on 26 of its 53 references that are in the map.
- First posted on arXiv 14 Aug 2025.

## Builds on (most cited first, 26 of 26)

- [BERT: Pre-training of Deep Bidirectional Transformers for Language Understanding](https://mlsanity.com/paper/1810.04805/) (2018)
- [Language Models are Few-Shot Learners](https://mlsanity.com/paper/2005.14165/) (2020)
- [Equivariant Diffusion for Molecule Generation in 3D](https://mlsanity.com/paper/2203.17003/) (2022)
- [Junction Tree Variational Autoencoder for Molecular Graph Generation](https://mlsanity.com/paper/1802.04364/) (2018)
- [Grokking: Generalization Beyond Overfitting on Small Algorithmic Datasets](https://mlsanity.com/paper/2201.02177/) (2022)
- [Benign Overfitting in Linear Regression](https://mlsanity.com/paper/1906.11300/) (2019)
- [GeoDiff: a Geometric Diffusion Model for Molecular Conformation Generation](https://mlsanity.com/paper/2203.02923/) (2022)
- [DiffDock: Diffusion Steps, Twists, and Turns for Molecular Docking](https://mlsanity.com/paper/2210.01776/) (2022)
- [GraphAF: a Flow-based Autoregressive Model for Molecular Graph Generation](https://mlsanity.com/paper/2001.09382/) (2020)
- [Towards Understanding Grokking: An Effective Theory of Representation Learning](https://mlsanity.com/paper/2205.10343/) (2022)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [Pocket2Mol: Efficient Molecular Sampling Based on 3D Protein Pockets](https://mlsanity.com/paper/2205.07249/) (2022)
- [GraphDF: A Discrete Flow Model for Molecular Graph Generation](https://mlsanity.com/paper/2102.01189/) (2021)
- [3D Equivariant Diffusion for Target-Aware Molecule Generation and Affinity Prediction](https://mlsanity.com/paper/2303.03543/) (2023)
- [A 3D Generative Model for Structure-Based Drug Design](https://mlsanity.com/paper/2203.10446/) (2022)
- [Generating 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2204.09410/) (2022)
- [DiffBP: Generative Diffusion of 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2211.11214/) (2022)
- [MolCRAFT: Structure-Based Drug Design in Continuous Parameter Space](https://mlsanity.com/paper/2404.12141/) (2024)
- [Geometry-Complete Diffusion for 3D Molecule Generation and Optimization](https://mlsanity.com/paper/2302.04313/) (2023)
- [Functional-Group-Based Diffusion for Pocket-Specific Molecule Generation and Elaboration](https://mlsanity.com/paper/2306.13769/) (2023)
- [ScaleLong: Towards More Stable Training of Diffusion Model via Scaling Network Long Skip Connection](https://mlsanity.com/paper/2310.13545/) (2023)
- [Structure-based drug design by denoising voxel grids](https://mlsanity.com/paper/2405.03961/) (2024)
- [CBGBench: Fill in the Blank of Protein-Molecule Complex Binding Graph](https://mlsanity.com/paper/2406.10840/) (2024)
- [Generalization in Neural Networks: A Broad Survey](https://mlsanity.com/paper/2209.01610/) (2022)
- [Model-agnostic Measure of Generalization Difficulty](https://mlsanity.com/paper/2305.01034/) (2023)
- [Dockformer: A transformer-based molecular docking paradigm for large-scale virtual screening](https://mlsanity.com/paper/2411.06740/) (2024)

## Built on by (most cited first, 1 of 1)

- [Sample Complexity of Transfer Learning: An Optimal Transport Approach](https://mlsanity.com/paper/2605.20545/) (2026)

## Abstract (arXiv)

Three-dimensional generative models increasingly drive structure-based drug discovery, yet it remains constrained by the scarce publicly available protein-ligand complexes. Under such data scarcity, almost all existing pipelines struggle to learn transferable geometric priors and consequently overfit to training-set biases. As such, we present IBEX, an Information-Bottleneck-EXplored coarse-to-fine pipeline to tackle the chronic shortage of protein-ligand complex data in structure-based drug design. Specifically, we use PAC-Bayesian information-bottleneck theory to quantify the information density of each sample. This analysis reveals how different masking strategies affect generalization and indicates that, compared with conventional de novo generation, the constrained Scaffold Hopping task endows the model with greater effective capacity and improved transfer performance. IBEX retains the original TargetDiff architecture and hyperparameters for training to generate molecules compatible with the binding pocket; it then applies an L-BFGS optimization step to finely refine each conformation by optimizing five physics-based terms and adjusting six translational and rotational degrees of freedom in under one second. With only these modifications, IBEX raises the zero-shot docking success rate on CBGBench CrossDocked2020-based from 53% to 64%, improves the mean Vina score from -7.41 kcal mol-1 to -8.07 kcal mol-1, and achieves the best median Vina energy in 57 of 100 pockets versus 3 for the original TargetDiff. IBEX also increases the QED by 25%, achieves state-of-the-art validity and diversity, and markedly reduces extrapolation error.