Probing biological mechanisms with chemical tools

[Display omitted] Traditionally small molecules have mainly been used to inhibit biochemical activities of proteins, however such compounds can also be used to change the conformational energy landscape of proteins. Tool compounds that modulate protein conformations often reveal unexpected biologica...

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Veröffentlicht in:	Pharmacological research 2020-03, Vol.153, p.104656, Article 104656
Hauptverfasser:	Kang, Congbao, Keller, Thomas H.
Format:	Artikel
Sprache:	eng
Schlagworte:	Allosteric inhibitors Binding Sites Chemical biology Drug discovery Drug Discovery - methods Hydrophobic and Hydrophilic Interactions Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - chemistry Models, Molecular Nuclear Proteins - antagonists & inhibitors Nuclear Proteins - chemistry Protein Conformation Protein Tyrosine Phosphatases - antagonists & inhibitors Protein Tyrosine Phosphatases - chemistry Proteins - antagonists & inhibitors Proteins - chemistry Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Structural biology Structure-Activity Relationship Transcription Factors - antagonists & inhibitors Transcription Factors - chemistry
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Zusammenfassung:	[Display omitted] Traditionally small molecules have mainly been used to inhibit biochemical activities of proteins, however such compounds can also be used to change the conformational energy landscape of proteins. Tool compounds that modulate protein conformations often reveal unexpected biological mechanisms, which have therapeutic potential. We discuss two examples where screening hits were found to bind to unexpected binding pockets on well known proteins, establishing new routes for the inhibition of proteins that were thought to be undruggable.
ISSN:	1043-6618 1096-1186
DOI:	10.1016/j.phrs.2020.104656