Review
Discovery of a new GLP-1 receptor agonist using DNA encoded-libraries and similarity search
Ju Ho Lee a,d,1, Doyoun Kim a,b,d,1, Hyejin Jeon c,1, Sung Bum Park a,d,1, Byumseok Koh a,b,d,1, Byungho Lim a,b,d,1, Kyeong A. Lee a,d, Kyoung Jin Choi a,d, Seong Soon Kim a,d, Yujin Kwon a,b,d, Jung-Hee Lim a,d, Jung Hyun Jo a,d, Yeonji Park a,d, Sunjong Yu a,d, Nam-Chul Cho a,d, Wan Namkung c,*, Yuno Lee a,d,, Hyun Jin Kim a,d,, Ki Young Kim a,d,, Jung-Nyoung Heo a,d,
a Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea
b Medicinal Chemistry & Pharmacology, Korea National University of Science & Technology (UST), Daejeon 34113, Republic of Korea
c College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Republic of Korea
d Department of DEL Technology, KRICT, Daejeon 34114, Republic of Korea
ARTICLE INFO
Edited by Dr G Liu
Keywords:
DNA-encoded libraries DEL
GLP-1R
Drug screening Diabetes Obesity
Highlights
- Study demonstrates that DEL screening combined with similarity analysis, biophysical validation, and structure-guided modeling can uncover novel small-molecule GLP-1R agonists.
ABSTRACT
The glucagon-like peptide-1 receptor (GLP-1R) is a validated therapeutic target for type 2 diabetes and obesity, yet discovery of orally available small-molecule agonists remains challenging. Here, we applied DNA-encoded library (DEL) technology to identify novel small-molecule binders and functional agonists of GLP-1R. Screening of DEL against recombinant GLP-1R revealed recurring structural motifs, particularly a chromane- containing building block. Selected high-scoring off-DNA compounds were synthesized and further expanded through similarity-based searches.
Functional evaluation using a cAMP assay in GLP-1R–expressing CHO-K1 cells identified KCB-C06 as a GLP-1R agonist that induced a receptor-specific, dose-dependent increase in intracellular cAMP. Direct binding of KCB- C06 to GLP-1R was confirmed by biolayer interferometry. Structure-based analyses revealed that KCB-C06 oc- cupies an orthosteric pocket partially overlapping with known small-molecule agonists, engaging key hydro- phobic and aromatic residues through π-stacking and backbone interactions.
Study demonstrates that DEL screening combined with similarity analysis, biophysical validation, and structure-guided modeling can uncover novel small-molecule GLP-1R agonists. These findings provide a foun- dation for subsequent structure–activity relationship optimization toward small-molecule based GLP-1R therapeutics.
Article
In this study, DEL-based screening was used for discovery of novel small-molecule agonists targeting GLP-1R. Unfortunately, no hit com- pound was identified when only DEL screening data and off-DNA syn- thesis with high score and frequency values were used.
These results suggest that KCB-C06 represents a small-molecule GLP- 1R agonist identified through DEL-based screening and similarity search, providing a foundation for further optimization and characterization.
Available online July 7, 2026
0147-6513/© 2026 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).