RT Journal Article
T1 Docking Screens for Dual Inhibitors of Disparate Drug Targets for Parkinson’s Disease
A1 Jaiteh, Mariama
A1 Zeifman, Alexey
A1 Saarinen, Marcus
A1 Svenningsson, Per
A1 Brea Floriani, José Manuel
A1 Loza García, María Isabel
A1 Carlsson, Jens
AB Modulation of multiple biological targets with a single drug can lead to synergistic therapeutic effects and has been demonstrated to be essential for efficient treatment of CNS disorders. However, rational design of compounds that interact with several targets is very challenging. Here, we demonstrate that structure-based virtual screening can guide the discovery of multi-target ligands of unrelated proteins relevant for Parkinson’s disease. A library with 5.4 million molecules was docked to crystal structures of the A2A adenosine receptor (A2AAR) and monoamine oxidase B (MAO-B). Twenty-four compounds that were among the highest ranked for both binding sites were evaluated experimentally, resulting in the discovery of four dual-target ligands. The most potent compound was an A2AAR antagonist with nanomolar affinity (Ki = 19 nM) and inhibited MAO-B with an IC50 of 100 nM. Optimization guided by the predicted binding modes led to the identification of a second potent dual-target scaffold. The two discovered scaffolds were shown to counteract 6-hydroxydopamine-induced neurotoxicity in dopaminergic neuronal-like SH-SY5Y cells. Structure-based screening can hence be used to identify ligands with specific polypharmacological profiles, providing new avenues for drug development against complex diseases.
PB American Chemical Society
YR 2018
FD 2018-05-24
LK https://hdl.handle.net/10347/45516
UL https://hdl.handle.net/10347/45516
LA eng
NO J. Med. Chem. 2018, 61, 12, 5269–5278
NO This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (Grant Agreement 715052). The work was also supported by grants from the Swedish Research Council (Grants 2013-5708 and 2017-4676) and the Science for Life Laboratory to J.C. Computational resources were provided by the Swedish National Infrastructure for Computing (SNIC). We thank OpenEye Scientific Software for the use of OEChem and OMEGA at no cost.
DS Minerva
RD 27 abr 2026