RT Journal Article
T1 Structure‐guided design of G‐Protein‐Coupled receptor polypharmacology
A1 Kampen, Stefanie
A1 Duy Vo, Duc
A1 Zhang, Xiaoqun
A1 Panel, Nicolas
A1 Yang, Yunting
A1 Jaiteh, Mariama
A1 Matricon, Pierre
A1 Svenningsson, Per
A1 Brea Floriani, José Manuel
A1 Loza García, María Isabel
A1 Kihlberg, Jan
A1 Carlsson, Jens
K1 Drug design
K1 Parkinson’s disease
K1 Polypharmacology
K1 Receptors
K1 Virtual screening
AB 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 A2A adenosine receptor and activate the D2 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
PB Wiley
YR 2021
FD 2021-04-27
LK https://hdl.handle.net/10347/45058
UL https://hdl.handle.net/10347/45058
LA eng
NO S. Kampen, D. Duy Vo, X. Zhang, N. Panel, Y. Yang, M. Jaiteh, P. Matricon, P. Svenningsson, J. Brea, M. I. Loza, J. Kihlberg, J. Carlsson, Angew. Chem. Int. Ed. 2021, 60, 18022
NO Swedish Research Council (2017-4676), the Swedish brain foundation (FO2019-0299), Xunta de Galicia (ED431C 2018/21), the Spanish Ministry of Science and Innovation (SAF2017-85225-C3-1-R), and the European Regional Development Fund (ERDF)
DS Minerva
RD 29 abr 2026