Efficient Sampling of PROTAC-Induced Ternary Complexes DOI Creative Commons
Hongtao Zhao, Stefan Schießer, Christian Tyrchan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Abstract Proteolysis targeting chimeras (PROTACs) are bifunctional small molecules that recruit an E3 ligase to a target protein, leading ubiquitin transfer and subsequent proteasomal degradation. The formation of ternary complexes is crucial step in PROTAC-induced protein degradation, gaining structural insights essential for rational PROTAC design. In this study, we present novel approach efficiently sampling complexes, which has been validated using 40 co-crystallized complex structures. comparison protein-protein docking-based integrative approaches, our method achieved impressive success rate 97% 50% retrospectively, measured by C α -RMSD the crystal structure within 10 4 Å, respectively, with average CPU time hours. Notably, utilizing unbound structures, values between predicted experimental structures were consistently 7 Å across six WDR5-PROTAC-VHL Our open-source software enables modeling single holds promise enhancing design efforts. TOC

Language: Английский

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

Xiaojuan Jia,

Bowen Tang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 289, P. 117432 - 117432

Published: Feb. 20, 2025

Language: Английский

Citations

0
Computational approaches to aid PROTAC drug discovery DOI

Sohini Chakraborti,

Kirsten McAulay

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Ternary Complex Modeling, Induced Fit Docking and Molecular Dynamics Simulations as a Successful Approach for the Design of VHL‐Mediated PROTACs Targeting the Kinase FLT3 DOI Creative Commons

Husam Nassar,

Anne‐Christin Sarnow,

İ. Çelik

et al.

Archiv der Pharmazie, Journal Year: 2025, Volume and Issue: 358(4)

Published: April 1, 2025

ABSTRACT Proteolysis targeting chimeras (PROTACs) have proven to be a novel approach for the degradation of disease‐causing proteins in drug discovery. One E3 ligases which efficient PROTACs been described is Von Hippel‐Lindau factor (VHL). However, development has so far often relied on minimum computational tools, that it mostly based trial‐and‐error process. Therefore, there great need resource‐ and time‐efficient structure‐based or approaches streamline PROTAC design. In this study, we present combined integrates static ternary complex formation, induced‐fit docking, molecular dynamics (MD) simulations. Our methodology was tested using four experimentally derived structures VHL PROTACs, reported BRD4, SMARCA2, FAK, WEE1. addition, applied validated model recently in‐house developed FLT3‐targeted (MA49). The results show models generated with protein–protein docking method implemented software MOE high predictive power reproducing experimental 3D structures. different active their respective showed reliability new VHL‐mediated degraders. particular, sensitive structural changes as evidenced by failed binding modes negative controls. Furthermore, MD simulations confirmed stability complexes emphasized importance dynamic studies understanding relationship between structure function.

Language: Английский

Citations

0
Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions DOI Creative Commons
Rajamanikkam Kamaraj, Subhrojyoti Ghosh,

Souvadra Das

et al.

Bioconjugate Chemistry, Journal Year: 2024, Volume and Issue: 35(8), P. 1089 - 1115

Published: July 11, 2024

Targeted protein degradation or TPD, is rapidly emerging as a treatment that utilizes small molecules to degrade proteins cause diseases. TPD allows for the selective removal of disease-causing proteins, including proteasome-mediated degradation, lysosome-mediated and autophagy-mediated degradation. This approach has shown great promise in preclinical studies now being translated treat numerous diseases, neurodegenerative infectious cancer. review discusses latest advances its potential new chemical modality immunotherapy, with special focus on innovative applications cutting-edge research PROTACs (Proteolysis TArgeting Chimeras) their efficient translation from scientific discovery technological achievements. Our also addresses significant obstacles prospects this domain, while offering insights into future immunotherapeutic applications.

Language: Английский

Citations

3
Computational methods and key considerations for in silico design of proteolysis targeting chimera (PROTACs) DOI
Amr E. Abbas, Fei Ye

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 277, P. 134293 - 134293

Published: July 29, 2024

Language: Английский

Citations

3
Property-based optimisation of PROTACs DOI
James S. Scott, Iacovos N. Michaelides, Markus Schade

et al.

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 7, 2024

PROTACs are an emerging therapeutic approach towards targeted protein degradation. This article examines the leading examples of this modality that in clinical development through prism their physicochemical properties.

Language: Английский

Citations

2
Binding of Peptides Containing D‐Amino Acids to the Tsg101 Tumor Susceptibility Protein DOI
Hugo Perez, Prem P. Chapagain, Bernard S. Gerstman

et al.

ChemistrySelect, Journal Year: 2024, Volume and Issue: 9(38)

Published: Oct. 1, 2024

Abstract Tsg101 is implicated in tumorigenesis and viral budding, its inhibition through peptide binding a potential therapeutic strategy. We utilized the crystal structure of Tsg101‐PSAP complex from protein databank molecular dynamics studies on peptide‐Tsg101 interactions. To enhance stability against enzymatic degradation, we designed peptides with L‐form terminal prolines D‐form middle amino acids. These also featured acetylated proline at N‐terminus amidated C‐terminus, increasing resistance to proteases. Virtual screening 400 acid combinations identified promising candidates specific sites. Subsequent simulations focused PywP, which displayed strong novel site. Further variations ′w’ showed that 18 21 tested peptides, notably PyeP PytP, remained firmly bound, highlighting their as inhibitors. contain hydrophilic residues, potentially improving solubility delivery.

Language: Английский

Citations

0
Efficient Sampling of PROTAC-Induced Ternary Complexes DOI Creative Commons
Hongtao Zhao, Stefan Schießer, Christian Tyrchan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Abstract Proteolysis targeting chimeras (PROTACs) are bifunctional small molecules that recruit an E3 ligase to a target protein, leading ubiquitin transfer and subsequent proteasomal degradation. The formation of ternary complexes is crucial step in PROTAC-induced protein degradation, gaining structural insights essential for rational PROTAC design. In this study, we present novel approach efficiently sampling complexes, which has been validated using 40 co-crystallized complex structures. comparison protein-protein docking-based integrative approaches, our method achieved impressive success rate 97% 50% retrospectively, measured by C α -RMSD the crystal structure within 10 4 Å, respectively, with average CPU time hours. Notably, utilizing unbound structures, values between predicted experimental structures were consistently 7 Å across six WDR5-PROTAC-VHL Our open-source software enables modeling single holds promise enhancing design efforts. TOC

Language: Английский

Citations

0