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Structure-Guided Sc...
Structure-Guided Screening for Functionally Selective D-2 Dopamine Receptor Ligands from a Virtual Chemical Library
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- Mannel, Barbara (författare)
- Friedrich Alexander Univ, Dept Chem & Pharm, Med Chem, Schuhstr 19, D-91052 Erlangen, Germany.
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- Jaiteh, Mariama (författare)
- Uppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab
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- Zeifman, Alexey (författare)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi,Science for Life Laboratory, SciLifeLab
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- Randakova, Alena (författare)
- Friedrich Alexander Univ, Dept Chem & Pharm, Med Chem, Schuhstr 19, D-91052 Erlangen, Germany.
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- Moller, Dorothee (författare)
- Friedrich Alexander Univ, Dept Chem & Pharm, Med Chem, Schuhstr 19, D-91052 Erlangen, Germany.
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- Hubher, Harald (författare)
- Friedrich Alexander Univ, Dept Chem & Pharm, Med Chem, Schuhstr 19, D-91052 Erlangen, Germany.
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- Gmeiner, Peter (författare)
- Friedrich Alexander Univ, Dept Chem & Pharm, Med Chem, Schuhstr 19, D-91052 Erlangen, Germany.
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- Carlsson, Jens (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Beräkningsbiologi och bioinformatik
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Friedrich Alexander Univ, Dept Chem & Pharm, Med Chem, Schuhstr 19, D-91052 Erlangen, Germany Beräkningsbiologi och bioinformatik (creator_code:org_t)
- 2017-09-19
- 2017
- Engelska.
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Ingår i: ACS Chemical Biology. - : AMER CHEMICAL SOC. - 1554-8929 .- 1554-8937. ; 12:10, s. 2652-2661
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via pathways associated with a therapeutic effect and avoid those causing side effects. Animal studies have indicated that ligands displaying functional selectivity at the D-2 dopamine receptor (D2R) could be safer and more efficacious drugs against neuropsychiatric diseases. In this work, computational design of functionally selective D2R ligands was explored using structure-based virtual screening. Molecular docking of known functionally selective ligands to a D2R homology model indicated that such compounds were anchored by interactions with the orthosteric site and extended into a common secondary pocket. A tailored virtual library with close to 13-000 compounds bearing 2,3-dichlorophenylpiperazine, a privileged orthosteric scaffold, connected to diverse chemical moieties via a linker was docked to the D2R model. Eighteen top-ranked compounds that occupied both the orthosteric and allosteric site were synthesized, leading to the discovery of 16 partial agonists. A majority of the ligands had comparable maximum effects in the G protein and beta-arrestin recruitment assays, but a subset displayed preference for a single pathway. In particular, compound 4 stimulated beta-arrestin recruitment (EC50 = 320 nM, E-max = 16%) but had no detectable G protein signaling. The use of structure-based screening and virtual libraries to discover GPCR ligands with tailored functional properties will be discussed.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
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