Integrative Modeling of PROTAC-Mediated Ternary Complexes
Abstract
Proteolysis-targeting chimeras (PROTACs), which selectively induce targeted protein degradation, represent an emerging drug discovery technology. Although numerous PROTACs have been reported, designing potent PROTACs still remains a great challenge, to some extent, due to insufficient structural data of Target-PROTAC-E3 ternary complexes. In this work, PROTAC-Model, an integrative computational method by combining the FRODOCK-based protocol and RosettaDock-based refinement, was developed to predict PROTAC-mediated ternary complex structures and tested on 14 cases. The quality of the models was evaluated using the criteria of the critical assessment of predicted interactions (CAPRI). Using the unbound structures, the FRODOCK-based protocol can generate the ternary complex structures with medium or high quality for 8 cases out of 14. With the refinement by RosettaDock, the cases with medium or high quality increase to 12. Compared with PRosettaC and the method developed by Drummond et al., PROTAC-Model shows better performance. In summary, PROTAC-Model should be useful for the rational design of PROTACs.
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Computational modeling to predict ternary complex formation is a promising in silico approach for monovalent interactions.
“Another promising in silico approach involves computational modeling to predict ternary complex formation, adapting strategies currently employed for PROtAc design to monovalent interactions (Zaidman et al. 2020;weng et al. 2021).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as weng et al. 2021
Weng et al. improved the aforementioned pipelines by combining FRODOCK's protein docking with filtering, re-scoring, and RosettaDock refinements.
“The aforementioned pipelines were subsequently improved by Weng et al. by combining FRODOCK's protein docking with rounds of filtering, re-scoring, and final RosettaDock's refinements.177”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [177]
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From serendipity to strategy: molecular glue degraders in cancer therapeutics
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“Another promising in silico approach involves computational modeling to predict ternary complex formation, adapting strategies currently employed for PROtAc design to monovalent interactions (Zaidman et al. 2020; weng et al. 2021). these are reviewed in detail elsewhere (Domostegui et al. 2022).”
- Authors
- Weng, G., Li, D., Kang, Y., & Hou, T.
- Affiliations
- Zhejiang University (CN)
- Corresponding author
- Kang, Yu
- Hou, Tingjun
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-10-28
- Volume
- 64
- Issue
- 21
- Pages
- 16271-16281
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W3211270181
- Cited by
- 130
- References
- 51
- Citations by year
- 2026: 26 · 2025: 32 · 2024: 26 · 2023: 22 · 2022: 24
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (21575128, 21907084, 81773632)
- Natural Science Foundation of Zhejiang Province (LZ19H300001)
- Fundamental Research Funds for the Central Universities (2020QNA7003)
- National Key R&D Program of China (2016YFA0501701, 2016YFB0201700)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- PROTACs, targeted protein degradation
- MeSH terms
- Humans, Drug Discovery, Mediator Complex, Proteolysis
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