Small-Molecule Stabilization of Protein-Protein Interactions: An Underestimated Concept in Drug Discovery?

The modulation of protein–protein interactions (PPIs) has been recognized as one of the most challenging tasks in drug discovery. While their systematic development has long been considered as intractable, this view has changed over the last years, with the first drug candidates undergoing clinical...

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Vydáno v:Angewandte Chemie International Edition Ročník 51; číslo 9; s. 2012 - 2018
Hlavní autoři: Thiel, Philipp, Kaiser, Markus, Ottmann, Christian
Médium: Journal Article
Jazyk:angličtina
Vydáno: Weinheim WILEY-VCH Verlag 27.02.2012
WILEY‐VCH Verlag
Wiley Subscription Services, Inc
Vydání:International ed. in English
Témata:
Animals
Biological Products - chemistry
Biological Products - pharmacology
Construction
drug design
Drug Discovery - methods
Drugs
Humans
Inhibitors
Medical research
Models, Molecular
Modulation
Modulators
Pharmaceutical industry
Protein Binding - drug effects
Protein Interaction Mapping
protein-protein interaction
Proteins
Proteins - chemistry
Proteins - metabolism
Recognition
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
small-molecule drugs
Stabilization
Strategy
Tasks
ISSN:1433-7851, 1521-3773, 1521-3773
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Shrnutí:The modulation of protein–protein interactions (PPIs) has been recognized as one of the most challenging tasks in drug discovery. While their systematic development has long been considered as intractable, this view has changed over the last years, with the first drug candidates undergoing clinical studies. To date, the vast majority of PPI modulators are interaction inhibitors. However, in many biological contexts a prolonged lifespan of a PPI might be desirable, calling for the complementary approach of PPI stabilization. In fact, nature offers impressive examples of this concept and some PPI‐stabilizing natural products have already found application as important drugs. Moreover, directed small‐molecule stabilization has recently been demonstrated. Therefore, it is time to take a closer look at the constructive side of modulating PPIs. Doing it the other way round: The modulation of protein–protein interactions (PPIs) by small molecules has become increasingly popular over the last few decades. However, “modulation” has mainly been perceived as “inhibition” of protein–protein interactions, omitting the complementary strategy of stabilizing such macromolecular complexes. This Minireview highlights amazing examples and the potential of this constructive side of modulating PPIs.
Bibliografie:istex:E33FA3FF3979F959188CEA3AC733E503A78E7397
Max Planck Society
In the general annotations to presented structure figures, SES is the solvent-excluded surface, and highlighted interaction surfaces are defined as surface patches within a distance of 3.5 Å next to the binding partner. All representations were generated with BALLView.1
ark:/67375/WNG-LSTZ08H7-N
ArticleID:ANIE201107616
DFG - No. OT 414/1-2
In the general annotations to presented structure figures, SES is the solvent‐excluded surface, and highlighted interaction surfaces are defined as surface patches within a distance of 3.5 Å next to the binding partner. All representations were generated with BALLView.
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ISSN:1433-7851
1521-3773
1521-3773
DOI:10.1002/anie.201107616