2. Academic Validation
  3. Discovery of novel aminopiperidinyl amide CXCR4 modulators through virtual screening and rational drug design

Discovery of novel aminopiperidinyl amide CXCR4 modulators through virtual screening and rational drug design

  • Eur J Med Chem. 2020 Sep 1;201:112479. doi: 10.1016/j.ejmech.2020.112479.
Yoon Hyeun Oum 1,  Steven A Kell 2,  Younghyoun Yoon 1,  Zhongxing Liang 1,  Pieter Burger 3,  Hyunsuk Shim 4
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 2 Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA 30322, USA; Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
  • 3 Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
  • 4 Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Radiology and Image Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Atlanta, GA 30322, USA. Electronic address: hshim@emory.edu.
PMID: 32534343 DOI: 10.1016/j.ejmech.2020.112479
Abstract

The C-X-C Chemokine Receptor type 4 (CXCR4) is a potential therapeutic target for HIV Infection, metastatic Cancer, and inflammatory autoimmune diseases. In this study, we screened the ZINC chemical database for novel CXCR4 modulators through a series of in silico guided processes. After evaluating the screened compounds for their binding affinities to CXCR4 and inhibitory activities against the chemoattractant CXCL12, we identified a hit compound (ZINC 72372983) showing 100 nM affinity and 69% chemotaxis inhibition at the same concentration (100 nM). To increase the potency of our hit compound, we explored the protein-ligand interactions at an atomic level using molecular dynamics simulation which enabled us to design and synthesize a novel compound (Z7R) with nanomolar affinity (IC50 = 1.25 nM) and improved chemotaxis inhibition (78.5%). Z7R displays promising anti-inflammatory activity (50%) in a mouse edema model by blocking CXCR4-expressed leukocytes, being supported by our immunohistochemistry study.

Keywords

C-X-C chemokine receptor type 4 (CXCR4); Chemokine modulator; Ligand shape similarity; Molecular docking; Molecular dynamics; Structure-based drug design.

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