Probing biological mechanisms with chemical tools

Congbao Kang; Thomas H Keller

doi:10.1016/j.phrs.2020.104656

Probing biological mechanisms with chemical tools

Pharmacol Res. 2020 Mar:153:104656. doi: 10.1016/j.phrs.2020.104656. Epub 2020 Jan 18.

Authors

Congbao Kang¹, Thomas H Keller²

Affiliations

¹ Experimental Drug Development Centre (EDDC), Agency for Science, Technology and Research (A*STAR), 10 Biopolis Road, Chromos, #05-01, 138670, Singapore.
² Experimental Drug Development Centre (EDDC), Agency for Science, Technology and Research (A*STAR), 10 Biopolis Road, Chromos, #05-01, 138670, Singapore. Electronic address: thkeller@eddc.a-star.edu.sg.

PMID: 31962154
DOI: 10.1016/j.phrs.2020.104656

Abstract

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.

Keywords: (E)-3-fluoro-N'-((5-(pyrimidin-2-ylthio)furan-2-yl)methylene) benzohydrazide (PubChem CID: 76554134); 2-chloro-1-[2-[3-(trifluoromethyl)anilino]phenyl]ethanone (PubChem CID: 137796964); Allosteric inhibitors; Chemical biology; Drug discovery; Flufenamic acid (PubChem CID: 3371); Iodoacetamide (PubChem CID: 3727); Structural biology.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Binding Sites
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*
Structure-Activity Relationship
Transcription Factors / antagonists & inhibitors
Transcription Factors / chemistry

Substances

Intracellular Signaling Peptides and Proteins
Nuclear Proteins
Proteins
Small Molecule Libraries
Transcription Factors
EYA2 protein, human
Protein Tyrosine Phosphatases