BibTex format
@article{Dollhopf:2026:10.1021/jacs.6c15228,
author = {Dollhopf, LC and Perrett, S and Schatz, D and Pickford, HD and Stomberg, V and Bartlett, EJ and Kallemeijn, WW and Walton, J and Deacon-Smith, N and Morrison, CR and Berezina, D and Gibson, RSL and Horrell, S and Bell, AS and Haycock, PR and Parsons, PJ and Tate, EW and van, Thor JJ and Fuchter, MJ},
doi = {10.1021/jacs.6c15228},
journal = {Journal ofthe American Chemical Society},
title = {Structure-BasedDesign with Arylazopyrazoles to EnableHigh-Affinity Photoswitchable Inhibitors of <i>N</i> -Myristoyltransferase},
url = {http://dx.doi.org/10.1021/jacs.6c15228},
year = {2026}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - <jats:title>Abstract</jats:title> <jats:p>Photopharmacology using photoswitches is a powerful way to reversibly control biological function with light, through the generation of photoswitchable synthetic ligands. While optimization of bioactive small molecules is increasingly driven by iterative experimental protein–ligand structures, structure-guided improvement in photoswitch photopharmacology using experimental structures remains rare. Here we report the development of the first photoswitchable inhibitors of the human enzyme N-myristoyltransferase 1 (HsNMT1), using an arylazopyrazole (AAP) as the switch motif. Through experimental structure-based design, we obtain inhibitors with single-digit nanomolar affinity for NMT, functional activity in cells, and good differential activity between E and Z photoswitch isomers. The availability of our highly potent ligands and protein–ligand structures, coupled with the excellent photoswitch properties of the AAP, allowed us to study the effect of protein binding on the switching events, including characterization of protein-bound Z → E photoisomerization kinetics for the first time. Overall, this study showcases the potential for structure-based design in photoswitch pharmacology, including understanding the dynamic consequences of target binding, paving the way for the development of advanced photopharmaceuticals.</jats:p>
AU - Dollhopf,LC
AU - Perrett,S
AU - Schatz,D
AU - Pickford,HD
AU - Stomberg,V
AU - Bartlett,EJ
AU - Kallemeijn,WW
AU - Walton,J
AU - Deacon-Smith,N
AU - Morrison,CR
AU - Berezina,D
AU - Gibson,RSL
AU - Horrell,S
AU - Bell,AS
AU - Haycock,PR
AU - Parsons,PJ
AU - Tate,EW
AU - van,Thor JJ
AU - Fuchter,MJ
DO - 10.1021/jacs.6c15228
PY - 2026///
SN - 0002-7863
TI - Structure-BasedDesign with Arylazopyrazoles to EnableHigh-Affinity Photoswitchable Inhibitors of <i>N</i> -Myristoyltransferase
T2 - Journal ofthe American Chemical Society
UR - http://dx.doi.org/10.1021/jacs.6c15228
UR - https://doi.org/10.1021/jacs.6c15228
ER -