Fragment-based drug discovery of small molecule ligands for the human chemokine CCL28. SLAS Discov 2023 Jun;28(4):163-169
Date
02/26/2023Pubmed ID
36841432Pubmed Central ID
PMC10339762DOI
10.1016/j.slasd.2023.02.004Scopus ID
2-s2.0-85149845436 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
The mucosal chemokine CCL28 is a promising target for immunotherapy drug development due to its elevated expression level in epithelial cells and critical role in creating and maintaining an immunosuppressive tumor microenvironment. Using sulfotyrosine as a probe, NMR chemical shift mapping identified a potential receptor-binding hotspot on the human CCL28 surface. CCL28 was screened against 2,678 commercially available chemical fragments by 2D NMR, yielding thirteen verified hits. Computational docking predicted that two fragments could occupy adjoining subsites within the sulfotyrosine recognition cleft. Dual NMR titrations confirmed their ability to bind CCL28 simultaneously, thereby validating an initial fragment pair for linking and merging strategies to design high-potency CCL28 inhibitors.
Author List
Zhou AL, Jensen DR, Peterson FC, Thomas MA, Schlimgen RR, Dwinell MB, Smith BC, Volkman BFAuthors
Michael B. Dwinell PhD Director, Professor in the Microbiology and Immunology department at Medical College of WisconsinFrancis C. Peterson PhD Professor in the Biochemistry department at Medical College of Wisconsin
Roman Schlimgen Postdoctoral Researcher in the Biochemistry department at Medical College of Wisconsin
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
ChemokinesChemokines, CC
Drug Discovery
Epithelial Cells
Humans
Ligands
