1. Cell-Based Selection Expands the Utility of DNA-Encoded Small-Molecule Library Technology to Cell Surface Drug Targets: Identification of Novel Antagonists of the NK3 Tachykinin Receptor
- Author
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Zining Wu, Sibongile Mataruse, Alex M. Tamburino, Gang Yao, Jeffrey A. Messer, Yun Ding, Jean Zhang, G Joseph Franklin, Jianghe Deng, Todd L. Graybill, Xin Zeng, David D. Wisnoski, Frank T. Coppo, David I. Israel, Genaro S. Scavello, Jennifer Summerfield, Andrew J. Pope, Michael Platchek, Vera Q. Bodmer, Paolo A. Centrella, Jing Chai, and Katie L Sargent Bedard
- Subjects
Cell ,Computational biology ,Acetates ,Ligands ,Small Molecule Libraries ,Structure-Activity Relationship ,medicine ,Humans ,Receptor ,Integral membrane protein ,G protein-coupled receptor ,Dose-Response Relationship, Drug ,Molecular Structure ,Drug discovery ,DNA-encoded chemical library ,Chemistry ,Receptors, Neurokinin-3 ,General Chemistry ,General Medicine ,DNA ,Combinatorial chemistry ,Small molecule ,medicine.anatomical_structure ,HEK293 Cells ,Quinolines ,Tachykinin receptor - Abstract
DNA-encoded small-molecule library technology has recently emerged as a new paradigm for identifying ligands against drug targets. To date, this technology has been used with soluble protein targets that are produced and used in a purified state. Here, we describe a cell-based method for identifying small-molecule ligands from DNA-encoded libraries against integral membrane protein targets. We use this method to identify novel, potent, and specific inhibitors of NK3, a member of the tachykinin family of G-protein coupled receptors (GPCRs). The method is simple and broadly applicable to other GPCRs and integral membrane proteins. We have extended the application of DNA-encoded library technology to membrane-associated targets and demonstrate the feasibility of selecting DNA-tagged, small-molecule ligands from complex combinatorial libraries against targets in a heterogeneous milieu, such as the surface of a cell.
- Published
- 2015