Structure-Based Identification of Novel Ligands Targeting Multiple Sites within a Chemokine-G-Protein-Coupled-Receptor Interface

Emmanuel W. Smith, Amanda M. Nevins, Zhen Qiao, Yan Liu, Anthony E. Getschman, Sai L. Vankayala, M. Trent Kemp, Francis C. Peterson, Rongshi Li, Brian F. Volkman, Yu Chen

Research output: Contribution to journalArticle

20 Scopus 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.

Original languageEnglish (US)
Pages (from-to)4342-4351
Number of pages10
JournalJournal of Medicinal Chemistry
Volume59
Issue number9
DOIs
StatePublished - May 12 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Smith, E. W., Nevins, A. M., Qiao, Z., Liu, Y., Getschman, A. E., Vankayala, S. L., Kemp, M. T., Peterson, F. C., Li, R., Volkman, B. F., & Chen, Y. (2016). Structure-Based Identification of Novel Ligands Targeting Multiple Sites within a Chemokine-G-Protein-Coupled-Receptor Interface. Journal of Medicinal Chemistry, 59(9), 4342-4351. https://doi.org/10.1021/acs.jmedchem.5b02042