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Cited by 21Computational Drug Discovery MethodsProtein Degradation and InhibitorsMachine Learning in Materials Science

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DiffInt: A Diffusion Model for Structure-Based Drug Design with Explicit Hydrogen Bond Interaction Guidance

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Sako, Masami, Yasuo, Nobuaki, Sekijima, Masakazu·2025·Journal of Chemical Information and Modeling
DOI 10.1021/acs.jcim.4c01385PMC PMC11733934

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Abstract

The design of drug molecules is a critical stage in the drug discovery process. The structure-based drug design has long played an important role in efficient development. Significant progress has been made in recent years in the generation of 3D molecules via deep generation models. However, while many existing models have succeeded in incorporating structural information on target proteins, they have not been able to address important interactions between protein and drug molecules, especially hydrogen bonds. In this study, we propose DiffInt as a novel structure-based approach that explicitly addresses interactions. The model naturally incorporates hydrogen bonds between protein and ligand molecules by treating them as pseudoparticles. The experimental results show that DiffInt reproduces hydrogen bonds, and the hydrogen binding energies significantly outperform those of existing models. To facilitate the use of our tool for generating new drug molecules based on any protein's three-dimensional structure, we have made the source code and trained model available on GitHub (https://github.com/sekijima-lab/DiffInt) under the MIT license, with the execution environment provided on Google Colab.

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Figures

Figure 1 Overview of DiffInt. The diffusion process adds noise to the data to obtain a latent noise representation, resulting in a Gaussian distribution at time step T in the center-of-gravity system of the input data. The generative process reconstructs the original data by gradually denoising the noise, and consequently also reconstructs the hydrogen bonds with the protein pocket. In both processes, the protein molecules and hydrogen bonding particles are treated as conditions and remain unchanged.
Figure 1 Overview of DiffInt. The diffusion process adds noise to the data to obtain a latent noise representation, resulting in a Gaussian distribution at time step T in the center-of-gravity system of the input data. The generative process reconstructs the original data by gradually denoising the noise, and consequently also reconstructs the hydrogen bonds with the protein pocket. In both processes, the protein molecules and hydrogen bonding particles are treated as conditions and remain unchanged.CC BY · PubMed Central
Figure 2 Introduction of interaction particles by considering hydrogen bonds as pseudoparticles. Two interaction particles are placed on each hydrogen bond (yellow dashed line) between the protein and ligand to provide information about the position and direction of the hydrogen bond. The red and yellow spheres indicate whether the ligand atom is electron-acceptor or electron-donor, respectively.
Figure 2 Introduction of interaction particles by considering hydrogen bonds as pseudoparticles. Two interaction particles are placed on each hydrogen bond (yellow dashed line) between the protein and ligand to provide information about the position and direction of the hydrogen bond. The red and yellow spheres indicate whether the ligand atom is electron-acceptor or electron-donor, respectively.CC BY · PubMed Central
Figure 3 Visualization of ligands with the target proteins (PDB IDs: 3cqw and 3c4f). (a,d) The reference ligand molecules binding to the proteins 3cqw and 4c4f, respectively. (b,c) Example ligands generated by the DiffInt for 3cqw. (e,f) Example ligands generated by the DiffInt for 3c4f. Upper panel in each figure shows 3D structures of the protein–ligand complexes and lower panel illustrates protein–ligand interaction.
Figure 3 Visualization of ligands with the target proteins (PDB IDs: 3cqw and 3c4f). (a,d) The reference ligand molecules binding to the proteins 3cqw and 4c4f, respectively. (b,c) Example ligands generated by the DiffInt for 3cqw. (e,f) Example ligands generated by the DiffInt for 3c4f. Upper panel in each figure shows 3D structures of the protein–ligand complexes and lower panel illustrates protein–ligand interaction.CC BY · PubMed Central
Figure 4 Prediction accuracy of hydrogen bond reproducibility for the four models. Each data point represents the average of hydrogen bond reproducibility for 100 molecules generated per pocket.
Figure 4 Prediction accuracy of hydrogen bond reproducibility for the four models. Each data point represents the average of hydrogen bond reproducibility for 100 molecules generated per pocket.CC BY · PubMed Central
Figure 5 Energy distribution of the best model of high affinity, displayed for each of the four models. Proportion of best models: Pocket2Mol: 4%, FLAG: 12%, DiffSBDD: 27%, DiffInt: 57%.
Figure 5 Energy distribution of the best model of high affinity, displayed for each of the four models. Proportion of best models: Pocket2Mol: 4%, FLAG: 12%, DiffSBDD: 27%, DiffInt: 57%.CC BY · PubMed Central
Figure 6 Number of data points becoming the best model for each model across strong, moderate, weak, and total regions.
Figure 6 Number of data points becoming the best model for each model across strong, moderate, weak, and total regions.CC BY · PubMed Central
Figure 7 Bond angle distributions for generated molecules and those in the test set. Density plots of the bond angles for (a) CCC, (b) CCO, (c) CNC, (d) OPO, (e) NCC, (f) CC=O, and (g) COC. Distributions are shown for molecules generated by four models (Pocket2Mol, FLAG, DiffSBDD, and DiffInt) and compared to the test set.
Figure 7 Bond angle distributions for generated molecules and those in the test set. Density plots of the bond angles for (a) CCC, (b) CCO, (c) CNC, (d) OPO, (e) NCC, (f) CC=O, and (g) COC. Distributions are shown for molecules generated by four models (Pocket2Mol, FLAG, DiffSBDD, and DiffInt) and compared to the test set.CC BY · PubMed Central
Figure 8 Dihedral angle distributions for generated molecules and those in the test set. Density plots of the dihedral angles for (a) CCCC, (b) cccc, (c) CCCO, (d) OCCO, (e) Cccc, and (f) CC=CC. Distributions are shown for molecules generated by four models (Pocket2Mol, FLAG, DiffSBDD, and DiffInt) and compared to the test set. The lower letters represent the atoms in the aromatic rings.
Figure 8 Dihedral angle distributions for generated molecules and those in the test set. Density plots of the dihedral angles for (a) CCCC, (b) cccc, (c) CCCO, (d) OCCO, (e) Cccc, and (f) CC=CC. Distributions are shown for molecules generated by four models (Pocket2Mol, FLAG, DiffSBDD, and DiffInt) and compared to the test set. The lower letters represent the atoms in the aromatic rings.CC BY · PubMed Central

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Citations

Cites

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Metadata

Authors
Sako, M., Yasuo, N., & Sekijima, M.
Affiliations
Institute of Science Tokyo (JP)
Corresponding author
Sekijima, Masakazu
ORCID
Venue
Journal of Chemical Information and Modeling
Publisher
American Chemical Society (ACS)
Published
2024-12-19
Volume
65
Issue
1
Pages
71-82
ISSN
  • 1549-9596 (ISSN-L)
  • 1549-960X
DOI
10.1021/acs.jcim.4c01385
PMC
PMC11733934
OpenAlex
W4405592636
Cited by
21
References
10
Citations by year
2026: 15 · 2025: 5 · 2024: 1
FWCI
4.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Chemical Information and Modeling (publishedVersion, cc-by)
  • ChemRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Japan Agency for Medical Research and Development (JP24ama121026)
  • Japan Society for the Promotion of Science (JP20H00620, JP24H01760)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Physical Sciences › Materials Science › Materials Chemistry › Machine Learning in Materials Science
Keywords
structure-based drug design, diffusion models, 3D molecule generation, hydrogen bonding, protein-ligand interactions, hydrogen binding energy, pseudoparticles
MeSH terms
Diffusion, Hydrogen Bonding, Ligands, Models, Molecular, Protein Conformation, Proteins, Software, Drug Design

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CoChat. (2026). Citation check: DiffInt: A Diffusion Model for Structure-Based Drug Design with Explicit Hydrogen Bond Interaction Guidance. https://app.cochat.ai/papers/10.1021/acs.jcim.4c01385
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Sako, M., Yasuo, N., & Sekijima, M. (2025). DiffInt: A Diffusion Model for Structure-Based Drug Design with Explicit Hydrogen Bond Interaction Guidance. Journal of Chemical Information and Modeling. https://doi.org/10.1021/acs.jcim.4c01385