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Docking Screens for Dual Inhibitors of Disparate Drug Targets for Parkinson's Disease
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-9229-5314
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Karolinska Inst, Dept Physiol & Pharmacol, Ctr Mol Med, SE-17177 Stockholm, Sweden.
Karolinska Inst, Dept Physiol & Pharmacol, Ctr Mol Med, SE-17177 Stockholm, Sweden.
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 12, p. 5269-5278Article in journal (Refereed) Published
Abstract [en]

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 A(2A) adenosine receptor (A(2A)AR) 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 A(2A)AR antagonist with nanomolar affinity (K-i = 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.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2018. Vol. 61, no 12, p. 5269-5278
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-361114DOI: 10.1021/acs.jmedchem.8b00204ISI: 000437811200015PubMedID: 29792714OAI: oai:DiVA.org:uu-361114DiVA, id: diva2:1250053
Funder
EU, Horizon 2020, 715052Swedish Research Council, 2013-5708Swedish Research Council, 2017-4676Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceAvailable from: 2018-09-21 Created: 2018-09-21 Last updated: 2018-09-21Bibliographically approved

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Jaiteh, MariamaCarlsson, Jens

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Computational Biology and BioinformaticsScience for Life Laboratory, SciLifeLabDepartment of Cell and Molecular Biology
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