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Structure-Based Identification of Novel Ligands Targeting Multiple Sites within a Chemokine-G-Protein-Coupled-Receptor Interface. J Med Chem 2016 05 12;59(9):4342-51

Date

04/09/2016

Pubmed ID

27058821

Pubmed Central ID

PMC5600900

DOI

10.1021/acs.jmedchem.5b02042

Scopus ID

2-s2.0-84969506287   17 Citations

Abstract

CXCL12 is a human chemokine that recognizes the CXCR4 receptor and is involved in immune responses and metastatic cancer. Interactions between CXCL12 and CXCR4 are an important drug target but, like other elongated protein-protein interfaces, present challenges for small molecule ligand discovery due to the relatively shallow and featureless binding surfaces. Calculations using an NMR complex structure revealed a binding hot spot on CXCL12 that normally interacts with the I4/I6 residues from CXCR4. Virtual screening was performed against the NMR model, and subsequent testing has verified the specific binding of multiple docking hits to this site. Together with our previous results targeting two other binding pockets that recognize sulfotyrosine residues (sY12 and sY21) of CXCR4, including a new analog against the sY12 binding site reported herein, we demonstrate that protein-protein interfaces can often possess multiple sites for engineering specific small molecule ligands that provide lead compounds for subsequent optimization by fragment based approaches.

Author List

Smith EW, Nevins AM, Qiao Z, Liu Y, Getschman AE, Vankayala SL, Kemp MT, Peterson FC, Li R, Volkman BF, Chen Y

Authors

Francis C. Peterson PhD 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

Binding Sites
Chemokine CXCL12
Humans
Ligands
Magnetic Resonance Spectroscopy
Molecular Structure
Receptors, CXCR4
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