# Generating 3D Binding Molecules Using Shape-Conditioned Diffusion Models with Guidance

arXiv: https://arxiv.org/abs/2502.06027 · HTML: https://mlsanity.com/paper/2502.06027/

## Key facts

- Cited by 10 papers in the map (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 33 of its 76 references that are in the map.
- First posted on arXiv 9 Feb 2025.

## Placed in

- Diffusion models / [Flow matching, time series and science](https://mlsanity.com/diffusion/flow-matching-time-series-and-science/)

## Builds on (most cited first, 30 of 33)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [GPT-4 Technical Report](https://mlsanity.com/paper/2303.08774/) (2023)
- [Denoising Diffusion Implicit Models](https://mlsanity.com/paper/2010.02502/) (2020)
- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Improved Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2102.09672/) (2021)
- [DeepSDF: Learning Continuous Signed Distance Functions for Shape Representation](https://mlsanity.com/paper/1901.05103/) (2019)
- [Dynamic Graph CNN for Learning on Point Clouds](https://mlsanity.com/paper/1801.07829/) (2018)
- [DiffWave: A Versatile Diffusion Model for Audio Synthesis](https://mlsanity.com/paper/2009.09761/) (2020)
- [Accelerating 3D Deep Learning with PyTorch3D](https://mlsanity.com/paper/2007.08501/) (2020)
- [Automatic chemical design using a data-driven continuous representation of molecules](https://mlsanity.com/paper/1610.02415/) (2016)
- [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)
- [Argmax Flows and Multinomial Diffusion: Learning Categorical Distributions](https://mlsanity.com/paper/2102.05379/) (2021)
- [Learning from Protein Structure with Geometric Vector Perceptrons](https://mlsanity.com/paper/2009.01411/) (2020)
- [Vector Neurons: A General Framework for SO(3)-Equivariant Networks](https://mlsanity.com/paper/2104.12229/) (2021)
- [Molecular Sets (MOSES): A Benchmarking Platform for Molecular Generation Models](https://mlsanity.com/paper/1811.12823/) (2018)
- [Equivariant Flows: Exact Likelihood Generative Learning for Symmetric Densities](https://mlsanity.com/paper/2006.02425/) (2020)
- [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)
- [3D Equivariant Diffusion for Target-Aware Molecule Generation and Affinity Prediction](https://mlsanity.com/paper/2303.03543/) (2023)
- [E(n) Equivariant Normalizing Flows](https://mlsanity.com/paper/2105.09016/) (2021)
- [A 3D Generative Model for Structure-Based Drug Design](https://mlsanity.com/paper/2203.10446/) (2022)
- [LlaSMol: Advancing Large Language Models for Chemistry with a Large-Scale, Comprehensive, High-Quality Instruction Tuning Dataset](https://mlsanity.com/paper/2402.09391/) (2024)
- [Geometric Deep Learning on Molecular Representations](https://mlsanity.com/paper/2107.12375/) (2021)
- [Generating 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2204.09410/) (2022)
- [DecompDiff: Diffusion Models with Decomposed Priors for Structure-Based Drug Design](https://mlsanity.com/paper/2403.07902/) (2024)
- [Generating 3D Molecules Conditional on Receptor Binding Sites with Deep Generative Models](https://mlsanity.com/paper/2110.15200/) (2021)
- [The Synthesizability of Molecules Proposed by Generative Models](https://mlsanity.com/paper/2002.07007/) (2020)
- [MolDiff: Addressing the Atom-Bond Inconsistency Problem in 3D Molecule Diffusion Generation](https://mlsanity.com/paper/2305.07508/) (2023)
- [A Deep Generative Model for Molecule Optimization via One Fragment Modification](https://mlsanity.com/paper/2012.04231/) (2020)

## Built on by (most cited first, 10 of 10)

- [LIDDIA: Language-based Intelligent Drug Discovery Agent](https://mlsanity.com/paper/2502.13959/) (2025)
- [Uncertainty-Aware Multi-Objective Reinforcement Learning-Guided Diffusion Models for 3D De Novo Molecular Design](https://mlsanity.com/paper/2510.21153/) (2025)
- [Generating Developable 3D Molecules via Pocket-Conditioned Diffusion and Property-Aware Optimization](https://mlsanity.com/paper/2607.12349/) (2026)
- [Planning with Diffusion Models for Target-Oriented Dialogue Systems](https://mlsanity.com/paper/2504.16858/) (2025)
- [Improving the accuracy and generalizability of molecular property regression models with a substructure-substitution-rule-informed framework](https://mlsanity.com/paper/2511.08314/) (2025)
- [Generative design and validation of therapeutic peptides for glioblastoma based on a potential target ATP5A](https://mlsanity.com/paper/2512.02030/) (2025)
- [Constraint-Aware Corrective Memory for Language-Based Drug Discovery Agents](https://mlsanity.com/paper/2604.09308/) (2026)
- [Tianmu-TC: Physics-constraints Generative Artificial Intelligence for Global Tropical Cyclone Forecasting](https://mlsanity.com/paper/2608.18500/) (2026)
- [A Systematic Evaluation of Molecule Generation Models for De Novo Drug Design: From Benchmarks to Practical Insights](https://mlsanity.com/paper/2609.10099/) (2026)
- [RIDE: Reference-Anchored Inference-Time Diffusion Editing for Scaffold Hopping](https://mlsanity.com/paper/2609.35623/) (2026)

## Abstract (arXiv)

Drug development is a critical but notoriously resource- and time-consuming process. In this manuscript, we develop a novel generative artificial intelligence (genAI) method DiffSMol to facilitate drug development. DiffSmol generates 3D binding molecules based on the shapes of known ligands. DiffSMol encapsulates geometric details of ligand shapes within pre-trained, expressive shape embeddings and then generates new binding molecules through a diffusion model. DiffSMol further modifies the generated 3D structures iteratively via shape guidance to better resemble the ligand shapes. It also tailors the generated molecules toward optimal binding affinities under the guidance of protein pockets. Here, we show that DiffSMol outperforms the state-of-the-art methods on benchmark datasets. When generating binding molecules resembling ligand shapes, DiffSMol with shape guidance achieves a success rate 61.4%, substantially outperforming the best baseline (11.2%), meanwhile producing molecules with novel molecular graph structures. DiffSMol with pocket guidance also outperforms the best baseline in binding affinities by 13.2%, and even by 17.7% when combined with shape guidance. Case studies for two critical drug targets demonstrate very favorable physicochemical and pharmacokinetic properties of the generated molecules, thus, the potential of DiffSMol in developing promising drug candidates.