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Structure-based Discovery of Novel US28 Small Molecule Ligands with Different Modes of Action
- Source :
- Lückmann, M, Amarandi, R-M, Papargyri, N, Jakobsen, M H, Christiansen, E, Jensen, L J, Pui, A, Schwartz, T W, Rosenkilde, M M & Frimurer, T M 2017, ' Structure-based Discovery of Novel US28 Small Molecule Ligands with Different Modes of Action ', Chemical Biology & Drug Design, vol. 89, no. 3, pp. 289–296 . https://doi.org/10.1111/cbdd.12848, Lückmann, M, Amarandi, R-M, Papargyri, N, Høy Jakobsen, M, Christiansen, E, Jensen, L J, Pui, A, Schwartz, T W, Rosenkilde, M M & Frimurer, T M 2017, ' Structure-based discovery of novel US28 small molecule ligands with different modes of action ', Chemical Biology and Drug Design, vol. 89, no. 3, pp. 289-296 . https://doi.org/10.1111/cbdd.12848
- Publication Year :
- 2017
-
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 Ca(2+) 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. This article is protected by copyright. All rights reserved.
- Subjects :
- Models, Molecular
0301 basic medicine
Agonist
Virtual screening
Molecular model
medicine.drug_class
Drug Evaluation, Preclinical
Molecular modeling
Ligands
01 natural sciences
Biochemistry
Small Molecule Libraries
Structure-Activity Relationship
Viral Proteins
03 medical and health sciences
Piperidines
Drug Discovery
medicine
Animals
Humans
Inverse agonist
G protein-coupled receptor
Pharmacology
Chemistry
Drug discovery
Organic Chemistry
chEMBL
Combinatorial chemistry
Small molecule
High-Throughput Screening Assays
0104 chemical sciences
010404 medicinal & biomolecular chemistry
030104 developmental biology
Drug Design
COS Cells
Molecular Medicine
Calcium
Receptors, Chemokine
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Lückmann, M, Amarandi, R-M, Papargyri, N, Jakobsen, M H, Christiansen, E, Jensen, L J, Pui, A, Schwartz, T W, Rosenkilde, M M & Frimurer, T M 2017, ' Structure-based Discovery of Novel US28 Small Molecule Ligands with Different Modes of Action ', Chemical Biology & Drug Design, vol. 89, no. 3, pp. 289–296 . https://doi.org/10.1111/cbdd.12848, Lückmann, M, Amarandi, R-M, Papargyri, N, Høy Jakobsen, M, Christiansen, E, Jensen, L J, Pui, A, Schwartz, T W, Rosenkilde, M M & Frimurer, T M 2017, ' Structure-based discovery of novel US28 small molecule ligands with different modes of action ', Chemical Biology and Drug Design, vol. 89, no. 3, pp. 289-296 . https://doi.org/10.1111/cbdd.12848
- Accession number :
- edsair.doi.dedup.....93841aab4af45c2b86e57923fe6f6b7a