ArticleJournal of chemical information and modeling2021
Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta.
Article in Journal of chemical information and modeling, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
62 citing papers in PubMed, 143 citations in OpenAlex.
- PROTACs in personalized and precision medicine: transforming targeted therapy with advances in selectivity and patient stratification.Cancer chemotherapy and pharmacology · 2026Review
- DesignMaster: a multi-conditional diffusion framework for rational PROTAC design.Bioinformatics (Oxford, England) · 2026Article
- COMPASS: A Computational Pipeline to Identify Linkers Predicting Ubiquitinable PROTAC-Induced Ternary Complexes.ChemMedChem · 2026Article
- Identification of a mechanism-based binding mode for a histone deacetylase 6 inhibitor.Nature communications · 2026Article
- Artificial intelligence driven protein design and sustainable nanomedicine for advanced theranostics.Bioactive materials · 2026Review
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- Metastable Protein-Protein Interactions as a Design Principle for PROTACs: Insights from the RIPK1-VHL System.JACS Au · 2026Article
- Interface Architecture of a VHL-PROTAC Complex with and without Cullin-2.Journal of the American Chemical Society · 2026Article
- From Serendipity to Strategy: Rationalizing Molecular Glue Discovery and Proximity-Induced Pharmacology through Chemical Biology.Journal of the American Chemical Society · 2026Review
- Computational Modeling of PROTAC Ternary Complexes as Ensembles Using SILCS-xTAC.Journal of chemical information and modeling · 2026Article
- AI-assisted design and virtual profiling of targeted degraders for pancreatic cancer therapy via PROTAC technology.American journal of cancer research · 2026Article
- Synthesis and Evaluation of AS1411-Lenalidomide-Targeted Degradation Chimera in Antitumor Therapy.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Mechanistic insights into PROTAC-mediated degradation through an integrated framework of molecular dynamics, free energy landscapes, and quantum mechanics: A case study on kinase degraders.Journal of computer-aided molecular design · 2025Article
- Construction of PROTAC-Mediated Ternary Complex Structure Distribution Profiles Using Extensive Conformational Search.Journal of chemical information and modeling · 2025Article
- Endogenous tyrosinase-catalyzed therapeutics.Nature communications · 2025Article
- Hijacking the MDM2 E3 Ligase with Novel BRD4-Targeting Proteolysis-Targeting Chimeras in Pancreatic Cancer Cells.Chembiochem : a European journal of chemical biology · 2025Article
- Accommodating Statistical and Physics-Based Computational Protocols for Molecular Glue Model and Evaluation.Journal of chemical information and modeling · 2025Article
- Unveiling New Triazoloquinoxaline-Based PROTACs Designed for the Selective Degradation of the ncBAF Chromatin Remodeling Subunit BRD9.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Quantum Mechanics-Based Ranking of Predicted Proteolysis Targeting Chimeras-Mediated Ternary Complexes.ACS medicinal chemistry letters · 2025Article
- Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 2 countries.
Funding
Abstract
Proteolysis-targeting chimaeras (PROTACs) are molecules that combine a target-binding warhead with an E3 ligase-recruiting moiety; by drawing the target protein into a ternary complex with the E3 ligase, PROTACs induce target protein degradation. While PROTACs hold exciting potential as chemical probes and as therapeutic agents, development of a PROTAC typically requires synthesis of numerous analogs to thoroughly explore variations on the chemical linker; without extensive trial and error, it is unclear how to link the two protein-recruiting moieties to promote formation of a productive ternary complex. Here, we describe a structure-based computational method for evaluating the suitability of a given linker for ternary complex formation. Our method uses Rosetta to dock the protein components and then builds the PROTAC from its component fragments into each binding mode; complete models of the ternary complex are then refined. We apply this approach to retrospectively evaluate multiple PROTACs from the literature, spanning diverse target proteins. We find that modeling ternary complex formation is sufficient to explain both activity and selectivity reported for these PROTACs, implying that other cellular factors are not key determinants of activity in these cases. We further find that interpreting PROTAC activity is best approached using an ensemble of structures of the ternary complex rather than a single static conformation and that members of a structurally conserved protein family can be recruited by the same PROTAC through vastly different binding modes. To encourage adoption of these methods and promote further analyses, we disseminate both the computational methods and the models of ternary complexes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.