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Ternary Complex-Templated Dynamic Combinatorial Chemistry for the Selection and Identification of Homo-PROTACs

Claudia Diehl, Alessandra Salerno, Alessio Ciulli

Version 2 posted 09 April 2024

We focus on VHL-targeting Homo -PROTACs as model system, and show that the formation of a VHL2:Homo -PROTAC ternary complex reversibly assembled using thiol-disulfide exchange chemistry leads to amplification of potent VHL Homo -PROTACs with degradation activities which correlated well with their biophysical ability to dimerize VHL. Ternary complex templated dynamic combinatorial libraries allowed identification of novel Homo -PROTAC degraders. We anticipate future applications of ternary -complex directed DCC to early PROTAC screenings and expansion to other proximity-inducing modalities beyond PROTACs

1,268

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Organic Chemistry

Working Paper

Reply to the Comment on “On the SN2 Reactions Modified in Vibrational Strong Coupling Experiments: Reaction Mechanisms and Vibrational Mode Assignments”

Clàudia Climent, Johannes Feist

Version 1 posted 28 April 2021

Lethuillier-Karl, J . Moran and T. Ebbesen, 2020, DOI :10.26434 /chemrxiv .12982358.v1.) on our recent paper (C . Climent and J . Feist, Phys. Chem . Chem . Phys., 2020, 22, 23545) had been posted to ChemRxiv

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2

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Catalysis

Working Paper

Gold-catalysed Heck Reactions: Fact or Fiction?

Peter H. M. Budzelaar, Manfred Bochmann, Martina Landrini, Luca Rocchigiani

Version 1 posted 10 January 2024

Two recent high-profile publications reported the formation of Heck-type arylated alkenes catalysed by MeDalPhosAuCl / AgOTf (J . Am. Chem . Soc. 2023 , 145, 8810) and their cyclisation to tetralines (Angew . Chem . Int . Ed . 2023 , e202312786). It was claimed that these were the first demonstrations in gold catalysis of alkene insertion into Au-aryl bonds, β-H elimination and chain-walking by Au-H cations. We show here that in fact this chemistry is a two-stage process. Only the first

852

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1

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Polymer Science

Working Paper

Monomer-Recyclable Polyesters From CO2 and 1,3-Butadiene

Jialin Xu, Yuxuan Niu, Bo-Lin Lin

Version 2 posted 13 March 2024

NOTE：This paper was first submitted for peer review at 31-Jan-2024 , Manu-script ID: ja-2024 -01537k. Recently, we found a very similar work published on ChemRxiv DOI : 10.26434 /chemrxiv -2024 -0p22l, therefore we decide to publish our work on ChemRxiv

358

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Biological and Medicinal Chemistry

Working Paper

Site-selective enzymatic C‒H amidation for synthesis of diverse lactams

Inha Cho, Zhijun Jia, Frances H. Arnold

Version 2 posted 03 January 2020

The original paper can be accessed by selecting “Version 1” of the preprint below, or by accessing https://doi.org/10.26434 /chemrxiv .7711418.v1. Inha Cho, Zhi-Jun Jia, Frances H. Arnold*Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.*Corresponding author. Email: [email protected]. I. Cho, Z.-J

2,688

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Analytical Chemistry

Working Paper

Proximity Biosensor Assay for PROTAC Ternary Complex Analysis

Irene Ponzo, Alice Solda, Charlotte Crowe, Goran Dahl, Stefan Geschwindner, Alessio Ciulli, Ulrich Rant

Version 1 posted 06 March 2024

Ternary complex stability is shown to arise from a dynamic interplay of associations and dissociations, suggesting that proximity assays can be utilized to identify weak interactions. The insights into proximity-mediated binding kinetics can enable the development of PROTACs

1,640

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Theoretical and Computational Chemistry

Working Paper

Non-Markovian Dynamic Models Identify Non-Canonical KRAS-VHL Encounter Complex Conformations for Novel PROTAC Design

Yunrui Qiu, Rafal P. Wiewiora, Jesus A. Izaguirre, Huafeng Xu, Woody Sherman, Weiping Tang, Xuhui Huang

Version 1 posted 11 June 2024

One notable method for TPD is Proteolysis Targeting Chimeras (PROTACs , or heterobifunctional degraders) that selectively degrade a protein of interest (POI) through E3-ligase induced ubiquitination followed by proteasomal degradation. PROTACs utilize a warhead-linker-ligand architecture to bring the POI (bound to the warhead) and the E3 ligase (bound to the ligand) into close proximity. The resulting non-native protein-protein interactions (PPIs) formed between the POI and E3 ligase lead to the formation of a stable POI-degrader-ligase ternary complex

542

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Biological and Medicinal Chemistry

Working Paper

Selection of DNA-encoded Chemical Libraries for Compounds that can Induce Protein Ubiquitination

Cen Huang, Xingyuan Liu, Xinyuan Wu, Ling Meng, Xiaojie Lu, Xiaoyu Li

Version 1 posted 12 February 2024

In this study, by selecting a DEL of 950 different combinations of POI ligands, linkers, and E3 ligase ligands against the BD1 domain of bromodomain-containing protein 4 (BRD4-BD1) in the presence and absence of ATP, we have identified a potent BRD4-BD1 degrader (DC50: ~9.7 nM) and also a short-isoform-selective BRD4 degrader (DC50: 0.26 μM). Furthermore, we show that the selection based on POI binding or ternary complex formation identified compounds that may have induced stable complexes

990

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Theoretical and Computational Chemistry

Working Paper

In Silico Modeling and Scoring of PROTAC-Mediated Ternary Complex Poses

Junzhuo Liao, Xueqing Nie, Ilona Unarta, Spencer Ericksen, Weiping Tang

Version 3 posted 20 December 2021

Proteolysis targeting chimeras (PROTACs ) are bifunctional molecules that induce ubiquitination and subsequent degradation of proteins via formation of ternary complexes between an E3 ubiquitin ligase and a target protein. Rational design of PROTACs requires accurate knowledge of the native configuration of the PROTAC induced ternary complex . This study demonstrates that native and non-native ternary complex poses can be distinguished based on pose occupancy time in MD, where native poses exhibit longer occupancy times than non-native ones at both room and higher temperatures. Candidate poses are generated by MD sampling and pre

1,962

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Theoretical and Computational Chemistry

Working Paper

Construction of PROTAC-Mediated Ternary Complex Structure Distribution Profiles Using Extensive Conformational Search

Genki Kudo, Takumi Hirao, Ryuhei Harada, Yasuteru Shigeta, Takatsugu Hirokawa, Ryunosuke Yoshino

Version 1 posted 17 April 2024

Proteolysis-targeting chimeras (PROTACs ) are heterobifunctional small molecules that recruit E3 ubiquitin ligases to a target protein and induce its ubiquitination by forming a ternary complex . For rational PROTAC design, computational methods that provide molecular insights into these association structures are required. In this study, we attempted extensive conformational search of PROTAC -mediated ternary complex structures using enhanced conformational sampling methods. Stable conformations were extracted from the molecular dynamics

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Ternary Complex-Templated Dynamic Combinatorial Chemistry for the Selection and Identification of Homo-PROTACs

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Reply to the Comment on “On the SN2 Reactions Modified in Vibrational Strong Coupling Experiments: Reaction Mechanisms and Vibrational Mode Assignments”

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Gold-catalysed Heck Reactions: Fact or Fiction?

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Monomer-Recyclable Polyesters From CO2 and 1,3-Butadiene

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Site-selective enzymatic C‒H amidation for synthesis of diverse lactams

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Proximity Biosensor Assay for PROTAC Ternary Complex Analysis

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Non-Markovian Dynamic Models Identify Non-Canonical KRAS-VHL Encounter Complex Conformations for Novel PROTAC Design

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Selection of DNA-encoded Chemical Libraries for Compounds that can Induce Protein Ubiquitination

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In Silico Modeling and Scoring of PROTAC-Mediated Ternary Complex Poses

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Construction of PROTAC-Mediated Ternary Complex Structure Distribution Profiles Using Extensive Conformational Search

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