uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Docking Finds GPCR Ligands in Dark Chemical Matter
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.ORCID iD: 0000-0002-4831-3423
Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden.
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. Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden.
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.
Show others and affiliations
2020 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 63, no 2, p. 613-620Article in journal (Refereed) Published
Abstract [en]

High-throughput screening has revealed dark chemical matter, a set of drug-like compounds that has never shown bioactivity despite being extensively assayed. If dark molecules are found active at a therapeutic target, their extraordinary selectivity profiles make excellent starting points for drug development. We explored if ligands of therapeutically relevant G-protein-coupled receptors could be discovered by structure-based virtual screening of the dark chemical matter. Molecular docking screens against crystal structures of the A(2A) adenosine and the D-4 dopamine receptors were carried out, and 53 top-ranked molecules were evaluated experimentally. Two ligands of each receptor were discovered, and the most potent had sub-micromolar affinities. Analysis of bioactivity data showed that the ligands lacked activity at hundreds of off-targets, including several that are associated with adverse effects. Our results demonstrate that virtual screening provides an efficient means to mine the dark chemical space, which could contribute to development of drugs with improved safety profiles.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2020. Vol. 63, no 2, p. 613-620
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-406186DOI: 10.1021/acs.jmedchem.9b01560ISI: 000509438800010PubMedID: 31846328OAI: oai:DiVA.org:uu-406186DiVA, id: diva2:1412482
Funder
EU, Horizon 2020, 715052Swedish Research Council, 2017-4676Available from: 2020-03-06 Created: 2020-03-06 Last updated: 2020-03-06Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Ballante, FlavioLuttens, AndreasVo, Duc DuyKihlberg, JanCarlsson, Jens

Search in DiVA

By author/editor
Ballante, FlavioLuttens, AndreasVo, Duc DuyKihlberg, JanCarlsson, Jens
By organisation
Science for Life Laboratory, SciLifeLabComputational Biology and BioinformaticsOrganic Chemistry
In the same journal
Journal of Medicinal Chemistry
Medicinal Chemistry

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 17 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf