Stabilization of protein-protein interactions in drug discovery

Introduction: PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the...

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Vydáno v:Expert opinion on drug discovery Ročník 12; číslo 9; s. 925 - 940
Hlavní autoři: Andrei, Sebastian A., Sijbesma, Eline, Hann, Michael, Davis, Jeremy, O'Mahony, Gavin, Perry, Matthew W. D., Karawajczyk, Anna, Eickhoff, Jan, Brunsveld, Luc, Doveston, Richard G., Milroy, Lech-Gustav, Ottmann, Christian
Médium: Journal Article
Jazyk:angličtina
Vydáno: England Taylor & Francis 02.09.2017
Témata:
Biological Products - pharmacology
Chemical biology
Drug Design
Drug Discovery - methods
druggable genome
Humans
medicinal chemistry
Pharmaceutical Preparations - chemical synthesis
Pharmaceutical Preparations - chemistry
Pharmaceutical Preparations - metabolism
PPI stabilization
PPIs
Protein Binding
Protein Stability
Proteins - metabolism
Small Molecule Libraries
small molecules
tool compounds
X-ray crystallography
Chemical biology
X-ray crystallography
druggable genome
tool compounds
PPI stabilization
medicinal chemistry
small molecules
PPIs
ISSN:1746-0441, 1746-045X, 1746-045X
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Shrnutí:Introduction: PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.
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ISSN:1746-0441
1746-045X
1746-045X
DOI:10.1080/17460441.2017.1346608