# DecompOpt: Controllable and Decomposed Diffusion Models for Structure-based Molecular Optimization

arXiv: https://arxiv.org/abs/2403.13829 · HTML: https://mlsanity.com/paper/2403.13829/

## Key facts

- Cited by 27 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 27 of its 54 references that are in the map.
- First posted on arXiv 7 Mar 2024.

## 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, 27 of 27)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Improved Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2102.09672/) (2021)
- [RePaint: Inpainting using Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2201.09865/) (2022)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [Junction Tree Variational Autoencoder for Molecular Graph Generation](https://mlsanity.com/paper/1802.04364/) (2018)
- [Molecular Sets (MOSES): A Benchmarking Platform for Molecular Generation Models](https://mlsanity.com/paper/1811.12823/) (2018)
- [Molecular De Novo Design through Deep Reinforcement Learning](https://mlsanity.com/paper/1704.07555/) (2017)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [Optimization of Molecules via Deep Reinforcement Learning](https://mlsanity.com/paper/1810.08678/) (2018)
- [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)
- [A 3D Generative Model for Structure-Based Drug Design](https://mlsanity.com/paper/2203.10446/) (2022)
- [MARS: Markov Molecular Sampling for Multi-objective Drug Discovery](https://mlsanity.com/paper/2103.10432/) (2021)
- [Equivariant 3D-Conditional Diffusion Models for Molecular Linker Design](https://mlsanity.com/paper/2210.05274/) (2022)
- [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)
- [Learning to Extend Molecular Scaffolds with Structural Motifs](https://mlsanity.com/paper/2103.03864/) (2021)
- [Augmenting Genetic Algorithms with Deep Neural Networks for Exploring the Chemical Space](https://mlsanity.com/paper/1909.11655/) (2019)
- [DiffBP: Generative Diffusion of 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2211.11214/) (2022)
- [Guiding Deep Molecular Optimization with Genetic Exploration](https://mlsanity.com/paper/2007.04897/) (2020)
- [Reinforced Genetic Algorithm for Structure-based Drug Design](https://mlsanity.com/paper/2211.16508/) (2022)
- [3DLinker: An E(3) Equivariant Variational Autoencoder for Molecular Linker Design](https://mlsanity.com/paper/2205.07309/) (2022)
- [Learning Subpocket Prototypes for Generalizable Structure-based Drug Design](https://mlsanity.com/paper/2305.13997/) (2023)
- [Zero-Shot 3D Drug Design by Sketching and Generating](https://mlsanity.com/paper/2209.13865/) (2022)
- [Scaffold-constrained molecular generation](https://mlsanity.com/paper/2009.07778/) (2020)
- [Structure-Based Drug Design via 3D Molecular Generative Pre-training and Sampling](https://mlsanity.com/paper/2402.14315/) (2024)

## Built on by (most cited first, 27 of 27)

- [On Statistical Rates and Provably Efficient Criteria of Latent Diffusion Transformers (DiTs)](https://mlsanity.com/paper/2407.01079/) (2024)
- [Diffusion Models in textitDe Novo Drug Design](https://mlsanity.com/paper/2406.08511/) (2024)
- [TAGMol: Target-Aware Gradient-guided Molecule Generation](https://mlsanity.com/paper/2406.01650/) (2024)
- [Reprogramming Pretrained Target-Specific Diffusion Models for Dual-Target Drug Design](https://mlsanity.com/paper/2410.20688/) (2024)
- [Decomposed Direct Preference Optimization for Structure-Based Drug Design](https://mlsanity.com/paper/2407.13981/) (2024)
- [Empower Structure-Based Molecule Optimization with Gradient Guided Bayesian Flow Networks](https://mlsanity.com/paper/2411.13280/) (2024)
- [General Binding Affinity Guidance for Diffusion Models in Structure-Based Drug Design](https://mlsanity.com/paper/2406.16821/) (2024)
- [Graph-structured Small Molecule Drug Discovery Through Deep Learning: Progress, Challenges, and Opportunities](https://mlsanity.com/paper/2502.08975/) (2025)
- [Differentially Private Kernel Density Estimation](https://mlsanity.com/paper/2409.01688/) (2024)
- [BoKDiff: Best-of-K Diffusion Alignment for Target-Specific 3D Molecule Generation](https://mlsanity.com/paper/2501.15631/) (2025)
- [Manipulating 3D Molecules in a Fixed-Dimensional E(3)-Equivariant Latent Space](https://mlsanity.com/paper/2506.00771/) (2025)
- [Unraveling the Potential of Diffusion Models in Small Molecule Generation](https://mlsanity.com/paper/2507.08005/) (2025)
- [HybridLinker: Topology-Guided Posterior Sampling for Enhanced Diversity and Validity in 3D Molecular Linker Generation](https://mlsanity.com/paper/2502.17349/) (2025)
- [Integrating Protein Dynamics into Structure-Based Drug Design via Full-Atom Stochastic Flows](https://mlsanity.com/paper/2503.03989/) (2025)
- [Designing Cyclic Peptides via Harmonic SDE with Atom-Bond Modeling](https://mlsanity.com/paper/2505.21452/) (2025)
- [Controllable 3D Molecular Generation for Structure-Based Drug Design Through Bayesian Flow Networks and Gradient Integration](https://mlsanity.com/paper/2508.21468/) (2025)
- [CAGenMol: Condition-Aware Diffusion Language Model for Goal-Directed Molecular Generation](https://mlsanity.com/paper/2604.11483/) (2026)
- [MF-LAL: Drug Compound Generation Using Multi-Fidelity Latent Space Active Learning](https://mlsanity.com/paper/2410.11226/) (2024)
- [Generating Developable 3D Molecules via Pocket-Conditioned Diffusion and Property-Aware Optimization](https://mlsanity.com/paper/2607.12349/) (2026)
- [Fragment-Masked Diffusion for Molecular Optimization](https://mlsanity.com/paper/2408.09106/) (2024)
- [TransDiffSBDD: Causality-Aware Multi-Modal Structure-Based Drug Design](https://mlsanity.com/paper/2503.20913/) (2025)
- [C-MORAL: Controllable Multi-Objective Molecular Optimization with Reinforcement Alignment for LLMs](https://mlsanity.com/paper/2604.23061/) (2026)
- [From Single-Step Edit Response to Multi-Step Molecular Optimization](https://mlsanity.com/paper/2605.10035/) (2026)
- [Fine-tuning Pocket-Aware Diffusion Models via Denoising Policy Optimization](https://mlsanity.com/paper/2605.17693/) (2026)
- [Fine-Tuning Diffusion Models for Molecular Generation via Reinforcement Learning and Fast Sampling](https://mlsanity.com/paper/2606.01220/) (2026)
- [SurfSpec: Enhancing Off-Target-Agnostic Specificity by Bounding Pocket-Ligand Geometric Mismatch](https://mlsanity.com/paper/2609.02963/) (2026)
- [One Sequence, Many Decodings: CAGenMol-2 Recasts Drug Design as Masked Molecular Inference](https://mlsanity.com/paper/2609.34301/) (2026)

## Abstract (arXiv)

Recently, 3D generative models have shown promising performances in structure-based drug design by learning to generate ligands given target binding sites. However, only modeling the target-ligand distribution can hardly fulfill one of the main goals in drug discovery -- designing novel ligands with desired properties, e.g., high binding affinity, easily synthesizable, etc. This challenge becomes particularly pronounced when the target-ligand pairs used for training do not align with these desired properties. Moreover, most existing methods aim at solving textitde novo design task, while many generative scenarios requiring flexible controllability, such as R-group optimization and scaffold hopping, have received little attention. In this work, we propose DecompOpt, a structure-based molecular optimization method based on a controllable and decomposed diffusion model. DecompOpt presents a new generation paradigm which combines optimization with conditional diffusion models to achieve desired properties while adhering to the molecular grammar. Additionally, DecompOpt offers a unified framework covering both textitde novo design and controllable generation. To achieve so, ligands are decomposed into substructures which allows fine-grained control and local optimization. Experiments show that DecompOpt can efficiently generate molecules with improved properties than strong de novo baselines, and demonstrate great potential in controllable generation tasks.