mlsanityData to 14 Oct 2026

A 3D pocket-aware and affinity-guided diffusion model for lead optimization

arXiv 2504.21065 ↗First posted 29 Apr 2025cs.LG cs.AIcited by 0

On the map: Diffusion models → Flow matching, time series and science

Abstract (arXiv)

Molecular optimization, aimed at improving binding affinity or other molecular properties, is a crucial task in drug discovery that often relies on the expertise of medicinal chemists. Recently, deep learning-based 3D generative models showed promise in enhancing the efficiency of molecular optimization. However, these models often struggle to adequately consider binding affinities with protein targets during lead optimization. Herein, we propose a 3D pocket-aware and affinity-guided diffusion model, named Diffleop, to optimize molecules with enhanced binding affinity. The model explicitly incorporates the knowledge of protein-ligand binding affinity to guide the denoising sampling for molecule generation with high affinity. The comprehensive evaluations indicated that Diffleop outperforms baseline models across multiple metrics, especially in terms of binding affinity.

Key facts. No citing papers in the map yet (data through 14 Oct 2026). Placed in Flow matching, time series and science, one of 14 directions in Diffusion models. Builds on 22 of its 52 references that are in the map. First posted on arXiv 29 Apr 2025.

Builds on

22 of 52 references.

Closest ancestors · 3

Same direction, newest first

  1. 2024DecompDiff: Diffusion Models with Decomposed Priors for Structure-Based Drug Design26 Feb
  2. 2022Structure-based Drug Design with Equivariant Diffusion Models24 Oct
  3. 2022Equivariant 3D-Conditional Diffusion Models for Molecular Linker Design11 Oct

Other references · 19

  1. 2020Score-Based Generative Modeling through Stochastic Differential Equationscited by 9,122
  2. 2021Diffusion Models Beat GANs on Image Synthesiscited by 8,255
  3. 2021Variational Diffusion Modelscited by 1,153
  4. 2021E(n) Equivariant Graph Neural Networkscited by 965
  5. 2020Directional Message Passing for Molecular Graphscited by 561
  6. 2019Analyzing Learned Molecular Representations for Property Predictioncited by 375
  7. 2017Molecular De Novo Design through Deep Reinforcement Learningcited by 267
  8. 2022Pocket2Mol: Efficient Molecular Sampling Based on 3D Protein Pocketscited by 183
  9. 20233D Equivariant Diffusion for Target-Aware Molecule Generation and Affinity Predictioncited by 177
  10. 2022A 3D Generative Model for Structure-Based Drug Designcited by 149
  11. 2022Generating 3D Molecules for Target Protein Bindingcited by 104
  12. 2021Generating 3D Molecules Conditional on Receptor Binding Sites with Deep Generative Modelscited by 73
7 more
  1. 2023MolDiff: Addressing the Atom-Bond Inconsistency Problem in 3D Molecule Diffusion Generationcited by 65
  2. 2022DiffBP: Generative Diffusion of 3D Molecules for Target Protein Bindingcited by 58
  3. 2020Optimizing Molecules using Efficient Queries from Property Evaluationscited by 50
  4. 2020A Deep Generative Model for Molecule Optimization via One Fragment Modificationcited by 37
  5. 2020Generating 3D Molecular Structures Conditional on a Receptor Binding Site with Deep Generative Modelscited by 33
  6. 2022Target-aware Molecular Graph Generationcited by 18
  7. 2024Deep Lead Optimization: Leveraging Generative AI for Structural Modificationcited by 10

Built on by

Not cited yet.

Similar, not cited

Close in wording, no citation either way

  1. 2025A 3D pocket-aware and evolutionary conserved interaction guided diffusion model for molecular optimization
  2. 2026Generating Developable 3D Molecules via Pocket-Conditioned Diffusion and Property-Aware Optimization
  3. 2026Fine-tuning Pocket-Aware Diffusion Models via Denoising Policy Optimization
  4. 2025Generating 3D Binding Molecules Using Shape-Conditioned Diffusion Models with Guidance
  5. 2024General Binding Affinity Guidance for Diffusion Models in Structure-Based Drug Design
  6. 2024DecompOpt: Controllable and Decomposed Diffusion Models for Structure-based Molecular Optimization
  7. 2025FLOWR.root: A flow matching based foundation model for joint multi-purpose structure-aware 3D ligand generation and affinity prediction
  8. 2022DiffDock: Diffusion Steps, Twists, and Turns for Molecular Docking