Target identification and understanding mechanism of action remains to be one of the biggest challenges in drug discovery pipeline. Photoaffinity labeling has been studied extensively for target identification, but the innate nonspecific protein labeling of the method can lead to false positives. In this study we have explored highly reactive Ligand Directed Tunable Michael acceptors (LDTMAc) with ester functional group. Modular design of LDTMAcs allowed us installation of the ligand on the ester functionality to design them as covalent inhibitors. On the other hand, installation of the ligand on the leaving group resulted in functionality installing probes that leave the active site unoccupied after the labeling reaction. Unlike other ligand directed approaches LDTMAcs’ reactivity is not limited to single amino acid, and they can modify single protein multiple times. These modifications were traced back to multiple histidine, serine, and lysine residues allowing us to map the ligand binding site. Target specificity of LDTMAcs was demonstrated by protein labeling in whole cell lysate. This work suggests the LDTMAcs could be used in identifying targets and binding sites of bio-active compounds.

Ligand directed protein labeling with tunable Michael acceptors

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.