Stabilized cyclic peptides as modulators of protein–protein interactions: promising strategies and biological evaluation DOI
Jiongjia Cheng, Junlong Zhou,

Lingyan Kong

et al.

RSC Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 14(12), P. 2496 - 2508

Published: Jan. 1, 2023

Protein-protein interactions (PPIs) control many essential biological pathways which are often misregulated in disease. As such, selective PPI modulators desirable to unravel complex functions of PPIs and thus expand the repertoire therapeutic targets. However, large size relative flatness interfaces make them challenging molecular targets for conventional drug modalities, rendering most "undruggable". Therefore, there is a growing need discover innovative molecules that able modulate crucial PPIs. Peptides ideal candidates deliver such therapeutics attributed their ability closely mimic structural features protein interfaces. inherently poor proteolysis resistance cell permeability inevitably hamper biomedical applications. The introduction constraint (

Language: Английский

Emerging landscape of molecular interaction networks: Opportunities, challenges and prospects DOI Open Access
Gauri Panditrao, Rupa Bhowmick, Chandrakala Meena

et al.

Journal of Biosciences, Journal Year: 2022, Volume and Issue: 47(2)

Published: April 20, 2022

Language: Английский

Citations

30
Molecular glues modulate protein functions by inducing protein aggregation: A promising therapeutic strategy of small molecules for disease treatment DOI Creative Commons
Hongyu Wu, Hong Yao,

Chen He

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2022, Volume and Issue: 12(9), P. 3548 - 3566

Published: March 31, 2022

Molecular glues can specifically induce aggregation between two or more proteins to modulate biological functions. In recent years, molecular have been widely used as protein degraders. addition, however, play a variety of vital roles, such complex stabilization, interactome modulation and transporter inhibition, enabling challenging therapeutic targets be druggable offering an exciting novel approach for drug discovery. Since most are identified serendipitously, exploration their systematic discovery rational design important. this review, representative examples with various physiological functions divided into those mediating homo-dimerization, homo-polymerization hetero-dimerization according modes, we attempt elucidate mechanisms action. particular, aim highlight some biochemical techniques typically exploited within these studies classify them in terms three stages glue development: starting point, optimization identification.

Language: Английский

Citations

29
Towards design of drugs and delivery systems with the Martini coarse-grained model DOI Creative Commons
Lisbeth R. Kjølbye, Gilberto P. Pereira, Alessio Bartocci

et al.

QRB Discovery, Journal Year: 2022, Volume and Issue: 3

Published: Jan. 1, 2022

Abstract Coarse-grained (CG) modelling with the Martini force field has come of age. By combining a variety bead types and sizes new mapping approach, newest version model is able to accurately simulate large biomolecular complexes at millisecond timescales. In this perspective, we discuss possible applications 3 in drug discovery development pipelines highlight areas for future development. Owing its high simulation efficiency extended chemical space, great potential area design delivery. However, several aspects should be improved before CG simulations can routinely employed academic industrial settings. These include automatic parameterisation protocols molecule types, improvement backmapping procedures, description protein flexibility methodologies enabling efficient sampling. We illustrate our view examples on key where could give important contributions such as drugs targeting membrane proteins, cryptic pockets protein–protein interactions soft delivery systems.

Language: Английский

Citations

29
Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence DOI Creative Commons
Miquel Duran‐Frigola, Marko Cigler, Georg E. Winter

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(5), P. 2711 - 2732

Published: Jan. 27, 2023

Only around 20% of the human proteome is considered to be druggable with small-molecule antagonists. This leaves some most compelling therapeutic targets outside reach ligand discovery. The concept targeted protein degradation (TPD) promises overcome these limitations. In brief, TPD dependent on small molecules that induce proximity between a interest (POI) and an E3 ubiquitin ligase, causing ubiquitination POI. this perspective, we want reflect current challenges in field, discuss how advances multiomics profiling, artificial intelligence, machine learning (AI/ML) will vital overcoming them. presented roadmap discussed context degraders but equally applicable for other emerging proximity-inducing modalities.

Language: Английский

Citations

21
Stabilized cyclic peptides as modulators of protein–protein interactions: promising strategies and biological evaluation DOI
Jiongjia Cheng, Junlong Zhou,

Lingyan Kong

et al.

RSC Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 14(12), P. 2496 - 2508

Published: Jan. 1, 2023

Protein-protein interactions (PPIs) control many essential biological pathways which are often misregulated in disease. As such, selective PPI modulators desirable to unravel complex functions of PPIs and thus expand the repertoire therapeutic targets. However, large size relative flatness interfaces make them challenging molecular targets for conventional drug modalities, rendering most "undruggable". Therefore, there is a growing need discover innovative molecules that able modulate crucial PPIs. Peptides ideal candidates deliver such therapeutics attributed their ability closely mimic structural features protein interfaces. inherently poor proteolysis resistance cell permeability inevitably hamper biomedical applications. The introduction constraint (

Language: Английский

Citations

17