title: Structure-Based Identification of Novel Ligands Targeting Multiple Sites within a Chemokine-G-Protein-Coupled-Receptor Interface.
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.
authors.affiliation: Department of Molecular Medicine, University of South Florida , 12901 Bruce B. Downs Boulevard, Tampa, Florida 33612, United States.
authors.forename: Emmanuel W
authors.initials: EW
authors.lastname: Smith
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Nevins
authors.affiliation: Department of Pharmaceutical Sciences, Center for Drug Discovery, College of Pharmacy, and Cancer Genes and Molecular Regulation Program, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center , 986805 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Qiao
authors.affiliation: Department of Pharmaceutical Sciences, Center for Drug Discovery, College of Pharmacy, and Cancer Genes and Molecular Regulation Program, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center , 986805 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Getschman
authors.affiliation: Department of Chemistry, University of South Florida , 4202 East Fowler Avenue, Tampa, Florida 33620, United States.
authors.forename: Sai L
authors.initials: SL
authors.lastname: Vankayala
authors.affiliation: Department of Chemistry, University of South Florida , 4202 East Fowler Avenue, Tampa, Florida 33620, United States.
authors.forename: M Trent
authors.initials: MT
authors.lastname: Kemp
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.
authors.forename: Francis C
authors.initials: FC
authors.lastname: Peterson
authors.affiliation: Department of Pharmaceutical Sciences, Center for Drug Discovery, College of Pharmacy, and Cancer Genes and Molecular Regulation Program, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center , 986805 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
authors.forename: Rongshi
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Volkman
authors.affiliation: Department of Molecular Medicine, University of South Florida , 12901 Bruce B. Downs Boulevard, Tampa, Florida 33612, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
mesh_terms: D001665:Binding Sites; D054377:Chemokine CXCL12 / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D019718:Receptors, CXCR4 / Q000378:metabolism*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D008024:Ligands; D019718:Receptors, CXCR4