title: Development of CXCR4 modulators by virtual HTS of a novel amide-sulfamide compound library.
abstract: CXCR4 plays a crucial role in recruitment of inflammatory cells to inflammation sites at the beginning of the disease process. Modulating CXCR4 functions presents a new avenue for anti-inflammatory strategies. However, using CXCR4 antagonists for a long term usage presents potential serious side effect due to their stem cell mobilizing property. We have been developing partial CXCR4 antagonists without such property. A new computer-aided drug design program, the FRESH workflow, was used for anti-CXCR4 lead compound discovery and optimization, which coupled both compound library building and CXCR4 docking screens in one campaign. Based on the designed parent framework, 30 prioritized amide-sulfamide structures were obtained after systemic filtering and docking screening. Twelve compounds were prepared from the top-30 list. Most synthesized compounds exhibited good to excellent binding affinity to CXCR4. Compounds Ig and Im demonstrated notable in vivo suppressive activity against xylene-induced mouse ear inflammation (with 56% and 54% inhibition). Western blot analyses revealed that Ig significantly blocked CXCR4/CXCL12-mediated phosphorylation of Akt. Moreover, Ig attenuated the amount of TNF-α secreted by pathogenic E. coli-infected macrophages. More importantly, Ig had no observable cytotoxicity. Our results demonstrated that FRESH virtual high throughput screening program of targeted chemical class could successfully find potent lead compounds, and the amide-sulfamide pharmacophore was a novel and effective framework blocking CXCR4 function.
authors.affiliation: Department of Radiation Oncology, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Renren
authors.initials: R
authors.lastname: Bai
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Radiation Oncology, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Radiation Oncology, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Younghyoun
authors.initials: Y
authors.lastname: Yoon
authors.affiliation: Department of Medicine, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Radiation Oncology, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Feng
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Shuangping
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Yoonhyeun
authors.initials: Y
authors.lastname: Oum
authors.affiliation: Department of Medicine, School of Medicine, Emory University, Atlanta, GA, USA; Winship Cancer Institute, Emory University, Atlanta, GA, USA; Atlanta VA Medical Center, Decatur, GA, USA.
authors.forename: C Chris
authors.initials: CC
authors.lastname: Yun
authors.affiliation: Department of Radiation Oncology, School of Medicine, Emory University, Atlanta, GA, USA; Winship Cancer Institute, Emory University, Atlanta, GA, USA; Department of Radiology and Imaging Science, Emory University School of Medicine, Atlanta, GA, USA. Electronic address: hshim@emory.edu.
authors.forename: Hyunsuk
authors.initials: H
authors.lastname: Shim
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D054377:Chemokine CXCL12 / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000188:drug therapy; D057166:High-Throughput Screening Assays; D051379:Mice; D062105:Molecular Docking Simulation; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014584:User-Computer Interface
chemical_list: D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt
keywords: Amide-sulfamide; Anti-inflammatory activity; CXCR4; Compound library building; Virtual HTS