DiffPROTACs is a deep learning-based generator for proteolysis targeting chimeras DOI Creative Commons
Fenglei Li,

Qiaoyu Hu,

Yongqi Zhou

и другие.

Briefings in Bioinformatics, Год журнала: 2024, Номер 25(5)

Опубликована: Июль 9, 2024

PROteolysis TArgeting Chimeras (PROTACs) has recently emerged as a promising technology. However, the design of rational PROTACs, especially linker component, remains challenging due to absence structure-activity relationships and experimental data. Leveraging structural characteristics fragment-based drug (FBDD) provides feasible approach for PROTAC research. Concurrently, artificial intelligence-generated content attracted considerable attention, with diffusion models Transformers emerging indispensable tools in this field. In response, we present new model, DiffPROTACs, harnessing power learn generate linkers based on given ligands. To introduce essential inductive biases required molecular generation, propose O(3) equivariant graph Transformer module, which augments neural networks (GNNs), using update nodes GNNs coordinates atoms. DiffPROTACs effectively competes existing achieves comparable performance two traditional FBDD datasets, ZINC GEOM. differentiate between PROTACs small molecules, fine-tuned model our self-built dataset, achieving 93.86% validity rate generated PROTACs. Additionally, provide database further research, can be accessed at https://bailab.siais.shanghaitech.edu.cn/service/DiffPROTACs-generated.tgz. The corresponding code is available https://github.com/Fenglei104/DiffPROTACs server https://bailab.siais.shanghaitech.edu.cn/services/diffprotacs.

Язык: Английский

Chasing molecular glue degraders: screening approaches DOI
Ana Domostegui, Luis Nieto‐Barrado, Carles Perez‐Lopez

и другие.

Chemical Society Reviews, Год журнала: 2022, Номер 51(13), С. 5498 - 5517

Опубликована: Янв. 1, 2022

By orchestrating interactions to an E3 ubiquitin ligase, molecular glue degraders have incredible therapeutic potential against otherwise “undruggable” proteins. We discuss how their discovery is evolving from serendipity intentional strategies.

Язык: Английский

Процитировано

106
Advancing Strategies for Proteolysis-Targeting Chimera Design DOI
Minglei Li, Ying Zhi, Bo Liu

и другие.

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(4), С. 2308 - 2329

Опубликована: Фев. 14, 2023

Proteolysis-targeting chimeras (PROTACs) have shown great therapeutic potential by degrading various disease-causing proteins, particularly those related to tumors. Therefore, the introduction of PROTACs has ushered in a new chapter antitumor drug development, marked significant advances over recent years. Herein, we describe developments PROTAC technology, focusing on design strategy, development workflow, and future outlooks. We also discuss opportunities challenges for research.

Язык: Английский

Процитировано

47
Characteristic roadmap of linker governs the rational design of PROTACs DOI Creative Commons
Yawen Dong, Tingting Ma, Ting Xu

и другие.

Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(10), С. 4266 - 4295

Опубликована: Апрель 11, 2024

Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected linker. The linker plays pivotal role determining PROTAC's biodegradative efficacy. Advanced and rationally designed linkers are under development. Nonetheless, correlation between characteristics efficacy remains under-investigated. Consequently, this study will present multidisciplinary analysis of their impact on efficacy, thereby guiding rational design linkers. We primarily discuss structural types linkers, optimization strategies used design. Furthermore, we how factors like length, group type, flexibility, linkage site affect biodegradation efficiency PROTACs. believe that work contribute towards advancement research area.

Язык: Английский

Процитировано

30
Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry DOI Creative Commons

Tom Dixon,

Derek MacPherson, Barmak Mostofian

и другие.

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Окт. 6, 2022

Targeted protein degradation (TPD) is a promising approach in drug discovery for degrading proteins implicated diseases. A key step this process the formation of ternary complex where heterobifunctional molecule induces proximity an E3 ligase to interest (POI), thus facilitating ubiquitin transfer POI. In work, we characterize 3 steps TPD process. (1) We simulate SMARCA2 bromodomain and VHL by combining hydrogen-deuterium exchange mass spectrometry with weighted ensemble molecular dynamics (MD). (2) conformational heterogeneity using Hamiltonian replica simulations small-angle X-ray scattering. (3) assess ubiquitination POI context full Cullin-RING Ligase, confirming experimental ubiquitinomics results. Differences efficiency can be explained lysine residues on relative ubiquitin.

Язык: Английский

Процитировано

68
Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation DOI
Jake A. Ward, Carles Perez‐Lopez, Cristina Mayor‐Ruiz

и другие.

ChemBioChem, Год журнала: 2023, Номер 24(10)

Опубликована: Апрель 5, 2023

Degraders have illustrated that compound-induced proximity to E3 ubiquitin ligases can prompt the ubiquitination and degradation of disease-relevant proteins. Hence, this pharmacology is becoming a promising alternative complement available therapeutic interventions (e. g., inhibitors). rely on protein binding instead inhibition and, hence, they hold promise broaden druggable proteome. Biophysical structural biology approaches been cornerstone understanding rationalizing degrader-induced ternary complex formation. Computational models now started harness experimental data from these with aim identify rationally help design new degraders. This review outlines current computational strategies used study formation highlights importance effective crosstalk between in advancement targeted (TPD) field. As our molecular features govern drug-induced interactions grows, faster optimizations superior innovations for TPD other proximity-inducing modalities are sure follow.

Язык: Английский

Процитировано

35
Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods DOI Creative Commons
Barmak Mostofian, Holli‐Joi Martin, Asghar M. Razavi

и другие.

Journal of Chemical Information and Modeling, Год журнала: 2023, Номер 63(17), С. 5408 - 5432

Опубликована: Авг. 21, 2023

The therapeutic approach of targeted protein degradation (TPD) is gaining momentum due to its potentially superior effects compared with inhibition. Recent advancements in the biotech and pharmaceutical sectors have led development compounds that are currently human trials, some showing promising clinical results. However, use computational tools TPD still limited, as it has distinct characteristics traditional drug design methods. involves creating a ternary structure (protein-degrader-ligase) responsible for biological function, such ubiquitination subsequent proteasomal degradation, which depends on spatial orientation interest (POI) relative E2-loaded ubiquitin. Modeling this necessitates unique blend initially developed small molecules (e.g., docking) biologics protein-protein interaction modeling). Additionally, degrader molecules, particularly heterobifunctional degraders, generally larger than conventional molecule drugs, leading challenges determining drug-like properties like solubility permeability. Furthermore, catalytic nature makes occupancy-based modeling insufficient. consists multiple interconnected yet steps, POI binding, E3 ligase interactions, ubiquitination, along properties. A comprehensive set needed address dynamic induced proximity complex implications ubiquitination. In Perspective, we discuss current state TPD. We start by describing series steps involved process experimental methods used characterize them. Then, delve into detailed analysis employed also present an integrative proven successful impact project decisions. Finally, examine future prospects areas greatest potential impact.

Язык: Английский

Процитировано

29
Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers DOI
Zehui Zhou,

Guizhen Zhou,

Chuan Zhou

и другие.

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(6), С. 4197 - 4214

Опубликована: Март 10, 2023

The linker moiety of a proteolysis-targeting chimera (PROTAC) molecule plays critical role in modulating the degradation activity, target selectivity, and physico-chemical properties. However, basics underlying mechanisms chemical modifications structure causing dramatic changes PROTAC activity warrant further investigation. Herein, we report design characterization highly potent selective SOS1 ZZ151. After systematically modifying length composition, observed that subtle modification just one atom ZZ151 resulted remarkable formation ternary complex thus dramatically affected activities. quickly, specifically, effectively induced degradation; displayed antiproliferation activities against broad panel KRAS mutant-driven cancer cells; showed superior anticancer KRASG12D- G12V-mutant xenografts mice. is promising lead for developing new chemotherapies targeting mutants.

Язык: Английский

Процитировано

26
In silico modeling of targeted protein degradation DOI Creative Commons
Wenxing Lv,

Xiaojuan Jia,

Bowen Tang

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 289, С. 117432 - 117432

Опубликована: Фев. 20, 2025

Язык: Английский

Процитировано

2
Quantum Mechanics-Based Ranking of Predicted Proteolysis Targeting Chimeras-Mediated Ternary Complexes DOI
Stefania Monteleone, Iñaki Morao, Dmitri G. Fedorov

и другие.

ACS Medicinal Chemistry Letters, Год журнала: 2025, Номер 16(3), С. 420 - 427

Опубликована: Фев. 6, 2025

Targeted protein degradation has become the most pursued alternative modality to small-molecule inhibition over past decade. The traditional strategy of blocking activity by tightly binding a functional substrate pocket progressed toward proteolysis-targeting chimeras (PROTACs), bivalent molecules that induce knockdown targeted proteins. Herein, combined protocol is described for modeling ternary complexes via well-established approaches. We performed local protein–protein docking using Rosetta and sampled conformational landscape specific PROTAC molecule was compatible with generated poses, followed double independent single-linkage/nearest-neighbor clustering representative selection. Subsequently, we fragment molecular orbital density tight-binding methods facilitate fast quantum mechanics-based energy calculations clustered complexes. Finally, computed values were utilized score select best achieving good agreement available crystallographic data.

Язык: Английский

Процитировано

1
Revolutionizing Drug Targeting Strategies: Integrating Artificial Intelligence and Structure-Based Methods in PROTAC Development DOI Creative Commons

Mohd Danishuddin,

Mohammad Sarwar Jamal, Kyoung Seob Song

и другие.

Pharmaceuticals, Год журнала: 2023, Номер 16(12), С. 1649 - 1649

Опубликована: Ноя. 24, 2023

PROteolysis TArgeting Chimera (PROTAC) is an emerging technology in chemical biology and drug discovery. This technique facilitates the complete removal of target proteins that are "undruggable" or challenging to through molecules via Ubiquitin-Proteasome System (UPS). PROTACs have been widely explored outperformed not only cancer but also other diseases. During past few decades, several academic institutes pharma companies poured more efforts into PROTAC-related technologies, setting stage for major degrader trial readouts clinical phases. Despite their promising results, formation robust ternary orientation, off-target activity, poor permeability, binding affinity some limitations hinder development. Recent advancements computational technologies facilitated progress development PROTACs. Researchers able utilize these explore a wider range E3 ligases optimize linkers, thereby gaining better understanding effectiveness safety settings. In this review, we briefly strategies reported date PROTAC components discuss key challenges opportunities further research area.

Язык: Английский

Процитировано

20