Open AccessCharacterization of Specific N-α-Acetyltransferase 50 (Naa50) Inhibitors Identified Using a DNA Encoded Library
Author(s) -
PeiPei Kung,
Patrick Bingham,
Benjamin J. Burke,
Qiuxia Chen,
Xue-Min Cheng,
Yao Deng,
Dengfeng Dou,
Junli Feng,
Gary M. Gallego,
Michael R. Gehring,
Stephan K. Grant,
S.E. Greasley,
Anthony R. Harris,
Karen A. Maegley,
Jordan L. Meier,
Xuan Meng,
José L Montaño,
Barry A. Morgan,
Brigitte S. Naughton,
Prakash B. Palde,
Thomas A. Paul,
Paul Richardson,
Sylvie K. Sakata,
Alex Shaginian,
William K. Sonnenburg,
Chakrapani Subramanyam,
Sergei Timofeevski,
Jinqiao Wan,
Wenshou Yan,
Albert Stewart
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00029
Subject(s) - cocrystal , substrate specificity , dna , computational biology , chemistry , acetyltransferase , mode of action , enzyme , mechanism of action , combinatorial chemistry , substrate (aquarium) , biochemistry , peptide , biology , gene , molecule , in vitro , acetylation , ecology , hydrogen bond , organic chemistry
Two novel compounds were identified as Naa50 binders/inhibitors using DNA-encoded technology screening. Biophysical and biochemical data as well as cocrystal structures were obtained for both compounds ( 3a and 4a ) to understand their mechanism of action. These data were also used to rationalize the binding affinity differences observed between the two compounds and a MLGP peptide-containing substrate. Cellular target engagement experiments further confirm the Naa50 binding of 4a and demonstrate its selectivity toward related enzymes (Naa10 and Naa60). Additional analogs of inhibitor 4a were also evaluated to study the binding mode observed in the cocrystal structures.