WFRF:(Jaiteh Mariama)
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Structure-Guided Design of G-Protein-Coupled Receptor Polypharmacology
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- Kampen, Stefanie (author)
- Uppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab
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- Vo, Duc Duy (author)
- Uppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab
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- Zhang, Xiaoqun (author)
- Karolinska Institutet,Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden.
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- (creator_code:org_t)
- 2021-07-16
- 2021
- English.
- In: Angewandte Chemie International Edition. - : John Wiley & Sons. - 1433-7851 .- 1521-3773. ; 60:33, s. 18022-18030
- Journal article (peer-reviewed)
Abstract
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- Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi-target profiles is rarely pursued because it is considered too difficult, in particular if the drug must enter the central nervous system. Here, a structure-based strategy to identify dual-target ligands of G-protein-coupled receptors is presented. We use this approach to design compounds that both antagonize the A(2A) adenosine receptor and activate the D-2 dopamine receptor, which have excellent potential as antiparkinson drugs. Atomic resolution models of the receptors guided generation of a chemical library with compounds designed to occupy orthosteric and secondary binding pockets in both targets. Structure-based virtual screens identified ten compounds, of which three had affinity for both targets. One of these scaffolds was optimized to nanomolar dual-target activity and showed the predicted pharmacodynamic effect in a rat model of Parkinsonism.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- drug design
- Parkinson's disease
- polypharmacology
- receptors
- virtual screening
Publication and Content Type
- ref (subject category)
- art (subject category)
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- Kampen, Stefanie
- Vo, Duc Duy
- Zhang, Xiaoqun
- Panel, Nicolas
- Yang, Yunting
- Jaiteh, Mariama
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- Matricon, Pierre
- Svenningsson, Pe ...
- Brea, Jose
- Loza, Maria Isab ...
- Kihlberg, Jan
- Carlsson, Jens
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- MEDICAL AND HEALTH SCIENCES
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- Uppsala University
- Karolinska Institutet
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