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Structure‐Guided Design of G‐Protein‐Coupled Receptor Polypharmacology
Author(s) -
Kampen Stefanie,
Duy Vo Duc,
Zhang Xiaoqun,
Panel Nicolas,
Yang Yunting,
Jaiteh Mariama,
Matricon Pierre,
Svenningsson Per,
Brea Jose,
Loza Maria Isabel,
Kihlberg Jan,
Carlsson Jens
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202101478
Subject(s) - virtual screening , adenosine a2a receptor , g protein coupled receptor , drug discovery , receptor , computational biology , chemistry , druggability , dopamine receptor d2 , pharmacology , adenosine receptor , dopamine , neuroscience , biology , biochemistry , gene , agonist
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.