YDS-Ternoplex: Surpassing AlphaFold 3-Type Models for Molecular Glue-Mediated Ternary Complex Prediction DOI Creative Commons
Xing Che

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

Published: Dec. 23, 2024

Abstract Molecular glues represent an innovative class of drugs that enable previously impossible protein-protein interactions, but their rational design remains challenging, a problem accurate ternary complex modeling can significantly address. Here we present YDS-Ternoplex, novel computational approach enhances AlphaFold 3-type models by incorporating enhanced sampling inductive bias during inference to accurately predict molecular glue-mediated structures. We demonstrate YDS-Ternoplex’s capabilities across five diverse test cases, including both E3 ligase-based systems (VHL:CDO1 and CRBN complexes with mTOR-FRB, NEK7, VAV1-SH3c) non-E3 ligase (FKBP12:mTOR-FRB). The model achieves remarkable accuracy RMSD values as low 1.303 Å compared experimental structures successfully predicts interfaces not in training data. Notably, the FKBP12:mTOR-FRB case, YDS-Ternoplex correctly interface configuration instead defaulting known interactions data, demonstrating strong generalization capabilities. Our results suggest strategic enhancement process through improve prediction accuracy, potentially accelerating development glue therapeutics for undruggable targets.

Language: Английский

Routes to molecular glue degrader discovery DOI Creative Commons
Yanfen Liu, Jieyun Bai, Dong Li

et al.

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

1
Mass Spectrometry Analysis of Chemically and Collisionally Dissociated Molecular Glue- and PROTAC-Mediated Protein Complexes Informs on Disassembly Pathways DOI
Edvaldo Vasconcelos Soares Maciel, Jonathan Eisert, J. Müller

et al.

Journal of the American Society for Mass Spectrometry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Molecular glues (MGs) and proteolysis-targeting chimeras (PROTACs) are used to modulate protein–protein interactions (PPIs), via induced proximity between compounds that have little or no affinity for each other naturally. They promote either reversible inhibition selective degradation of a target protein, including ones deemed undruggable by traditional therapeutics. Though native MS (nMS) is capable analyzing multiprotein complexes, the behavior these artificially in gas phase still not fully understood, number publications over past few years rather limited. Here, we studied two MG-induced complexes mTORFRB FKBP12 as well PROTAC-induced complex FKBP51FK1 von Hippel-Lindau E3 ligase (VHL). Native combined with collision-induced dissociation (CID) provided way measuring only formation but also their pathways. Both protein seem eject preferably centrally located small (compared mass proteins) ligand upon CID, than dissociating peripheral subunit, often observed naturally occurring complexes. In contrast, chemically solution generated complementary data disrupting PPI surface, which resulted more diverse spectra preserved stronger solution.

Language: Английский

Citations

1
Leveraging Structural and Computational Biology for Molecular Glue Discovery DOI Creative Commons
CongBao Kang, Weijun Xu

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

The discovery of molecular glues has made significant strides, unlocking new avenues for targeted protein degradation as a therapeutic strategy, thereby expanding the scope drug into territories previously considered undruggable. Pioneering molecules like thalidomide and its derivatives have paved way development small that can induce specific by hijacking cellular ubiquitin–proteasome system. Recent advancements focused on range E3 ligases target proteins be modulated glues. Structural elucidation ligase in complex with glue interest, combined computational modeling, facilitates understanding underlying mechanisms how degradation. By leveraging these tools, next generation are expected to offer unprecedented opportunities combating wide diseases, including cancer, autoimmune disorders, neurodegenerative conditions.

Language: Английский

Citations

1
Single-Molecule-Based, Label-Free Monitoring of Molecular Glue Efficacies for Promoting Protein–Protein Interactions Using YaxAB Nanopores DOI Creative Commons

Minju Ryu,

Sohee Oh, Ki‐Baek Jeong

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(45), P. 31451 - 31465

Published: Nov. 1, 2024

Modulating protein–protein interactions (PPIs) is an attractive strategy in drug discovery. Molecular glues, bifunctional small-molecule drugs that promote PPIs, offer approach to targeting traditionally undruggable targets. However, the efficient discovery of molecular glues has been hampered by current limitations conventional ensemble-averaging-based methods. In this study, we present a YaxAB nanopore for probing efficacy inducing PPIs. Using nanopores, demonstrate single-molecule-based, label-free monitoring protein complex formation between mammalian target rapamycin (mTOR) and FK506-binding proteins (FKBPs) triggered glue, rapamycin. Owing its wide entrance adjustable pore size, combination with potent electro-osmotic flow (EOF), single funnel-shaped enables simultaneous detection single-molecule-level quantification multiprotein states, including proteins, binary complexes, ternary complexes induced Notably, nanopores could sensitively discriminate or analogues, despite subtle size differences ∼122 ∼116 Da, respectively. Taken together, our results provide proof-of-concept label-free, ultrasensitive screening structure–activity relationship (SAR) analysis which will contribute low-cost, highly discovery, rational design modality drugs, such as glues.

Language: Английский

Citations

4
Research advancements in molecular glues derived from natural product scaffolds: Chemistry, targets, and molecular mechanisms DOI Open Access

Lina Yin,

Tingting Niu, Ling Li

et al.

Chinese Herbal Medicines, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Molecular Glues: A New Approach to Modulating GPCR Signaling Bias DOI Creative Commons

Jamie Kushnir,

Ryan H. Gumpper

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

G-protein-coupled receptors (GPCRs) transmit an extracellular chemical/biological signal across the cell membrane, stimulating array of intracellular signaling cascades. Canonically, these molecules bind to endogenous ligand pocket (orthosteric pocket), which stabilizes either active or inactive conformational ensemble receptor. However, recent structural evidence indicates that small can mediate protein–protein interactions between GPCR and their transducers. These are reminiscent molecular glues be powerful tools for modulating bias. In this Perspective, we will investigate current information available on how they modulate We also examine prospects drug/probe design.

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
Application of DELs for E3 Ligase Ligand Discovery and Targeted Protein Degradation DOI
Marie L. Malone,

Nicholas A. Sanchez,

Shimin Hu

et al.

Royal Society of Chemistry eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 134 - 156

Published: Feb. 21, 2025

Targeted protein degradation (TPD) provides new therapeutic opportunities beyond traditional inhibitors. TPD relies on the ability to induce proximity between an E3 ligase and target of interest, harnessing ubiquitin proteasome system ubiquitylate degrade target. This can be induced by either monofunctional ligands (molecular glues) or bifunctional molecules that tether ligases together. DNA encoded libraries (DELs) provide rapid access diverse chemical space for ligand discovery and, their design, facilitate development both molecular glues degraders.

Language: Английский

Citations

0
The “three body solution”: Structural insights into molecular glues DOI Creative Commons
Aidan C.A. Tomlinson, John E. Knox, Luc Brunsveld

et al.

Current Opinion in Structural Biology, Journal Year: 2025, Volume and Issue: 91, P. 103007 - 103007

Published: Feb. 26, 2025

Language: Английский

Citations

0
Leveraging efficiency metrics for the optimization of CELMoDs™ as cereblon-based molecular glue degraders DOI
Lei Jia, Jennifer R. Riggs, Dahlia R. Weiss

et al.

RSC Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Efficiency metrics are useful in medicinal chemistry to track small molecule progress lead optimization (LO). Molecular glue degraders molecules that mediate targeted protein degradation by chemically inducing proximity between an E3 ligase and a target. The potency depth of important factors identifying molecular drug candidates. We developed efficiency based on both objectives. applied these retrospectively clinical degrader series, resulting the identification Golcadomide (CC-99282). This work illustrates beneficial for

Language: Английский

Citations

0