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Improving Stereochemical Limitations in Protein-Ligand Complex Structure Prediction
Open accessPreprint — published as 10.1021/acsomega.5c07675 · Paper page
Abstract
AlphaFold3 has revolutionized biology by enabling the prediction of protein complexes with various biomolecules, including small molecular ligands. However, the ligand structures predicted by the model often contain stereochemical errors. In this study, our comprehensive evaluation of AlphaFold3 and its clone model, Boltz-1, demonstrated significant limitations in ligand stereochemistry of their predicted structures, including chirality, bond, and angle geometries. To address the issue, we developed the restraint-guided inference method that applies stereochemical restraints during the reverse diffusion process. This approach perfectly reproduces the chirality specified in the input chemical structure and improves bond and angle geometries of ligands, while maintaining comparable performance in binding pose prediction. Our method provides a practical solution to the stereochemical errors in predicting protein-ligand complexes, thereby enhancing applications of structure prediction in structural biology and drug discovery.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Ishitani, R., & Moriwaki, Y.
- Affiliations
- Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo (JP)
- Corresponding author
- Ishitani, Ryuichiro
- Venue
- ACS Omega
- Publisher
- openRxiv
- Published
- 2025-03-28
- Volume
- 10
- Issue
- 46
- Pages
- 56075-56084
- ISSN
- 2470-1343 (ISSN-L)
- OpenAlex
- W4416673658
- Cited by
- 19
- References
- 1
- Citations by year
- 2026: 15 · 2025: 3
- FWCI
- 5.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- creativecommons.org/licenses/by/4.0/ (vor)
- Locations
- ACS Omega (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- the Research Support Project for Life Science and Drug Discovery (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED (JP25ama121027, JP25ama121012)
- JSPS KAKENHI Grant-in-Aid (25H01570, 25H02250)
- the Medical Research Center Initiative for High Depth Omics at the Institute of Science Tokyo
- Nanken-Kyoten at the Institute of Science Tokyo
- the Multilayered Stress Diseases project (JPMXP1323015483)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- ligand chirality, AlphaFold3, reverse diffusion, binding pose prediction, bond lengths and angles
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