title: Structure-based discovery of novel US28 small molecule ligands with different modes of action.
abstract: The human cytomegalovirus-encoded G protein-coupled receptor US28 is a constitutively active receptor, which can recognize various chemokines. Despite the recent determination of its 2.9 Å crystal structure, potent and US28-specific tool compounds are still scarce. Here, we used structural information from a refined US28:VUF2274 complex for virtual screening of >12 million commercially available small molecule compounds. Using a combined receptor- and ligand-based approach, we tested 98 of the top 0.1% ranked compounds, revealing novel chemotypes as compared to the ~1.45 million known ligands in the ChEMBL database. Two compounds were confirmed as agonist and inverse agonist, respectively, in both IP accumulation and Ca2+mobilization assays. The screening setup presented in this work is computationally inexpensive and therefore particularly useful in an academic setting as it enables simultaneous testing in binding as well as in different functional assays and/or species without actual chemical synthesis.
authors: Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.|Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors: Michael
authors: M
authors: Lückmann
authors: Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.|Faculty of Chemistry, Alexandru Ioan Cuza University of Iaşi, Iaşi, Romania.
authors: Roxana-Maria
authors: RM
authors: Amarandi
authors: Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.|Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors: Natalia
authors: N
authors: Papargyri
authors: Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors: Mette H
authors: MH
authors: Jakobsen
authors: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
authors: Elisabeth
authors: E
authors: Christiansen
authors: Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
authors: Lars J
authors: LJ
authors: Jensen
authors: Faculty of Chemistry, Alexandru Ioan Cuza University of Iaşi, Iaşi, Romania.
authors: Aurel
authors: A
authors: Pui
authors: Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.|Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors: Thue W
authors: TW
authors: Schwartz
authors: Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors: Mette M
authors: MM
authors: Rosenkilde
authors: Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.|Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
authors: Thomas M
authors: TM
authors: Frimurer
mesh_terms: D000818:Animals; D019556:COS Cells / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism; D019707:Receptors, Chemokine / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D010880:Piperidines; D019707:Receptors, Chemokine; D054852:Small Molecule Libraries; C411191:US28 receptor, Cytomegalovirus; C473351:VUF 2274; D014764:Viral Proteins; D002118:Calcium
keywords: G protein-coupled receptor; drug discovery; molecular modeling; virtual screening