Docking Finds GPCR Ligands in Dark Chemical Matter

Ballante, Flavio (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Beräkningsbiologi och bioinformatik

Rudling, Axel (author): Stockholms universitet,Institutionen för biokemi och biofysik,Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden

Zeifman, Alexey (author): Uppsala universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Uppsala University, Sweden,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab,Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden

Luttens, Andreas (author): Uppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab

Vo, Duc Duy (author): Uppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab

Irwin, John J. (author): Univ Calif San Francisco, Dept Pharmaceut Chem, Byers Hall,1700 4th St, San Francisco, CA 94158 USA

Brea, Jose (author): Univ Santiago de Compostela, Ctr Res Mol Med & Chron Dis, Innopharma Screening Platform BioFarma Res Grp, Santiago De Compostela 15706, Spain

Isabel Loza, Maria (author): Univ Santiago de Compostela, Ctr Res Mol Med & Chron Dis, Innopharma Screening Platform BioFarma Res Grp, Santiago De Compostela 15706, Spain

Carlsson, Jens (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Beräkningsbiologi och bioinformatik

(creator_code:org_t)

2019-12-17
2020
English.
In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 63:2, s. 613-620

Related links:: https://urn.kb.se/re...; show more...; https://doi.org/10.1...; https://urn.kb.se/re...; show less...

Abstract Subject headings

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.

By the author/editor: Ballante, Flavio; Rudling, Axel; Zeifman, Alexey; Luttens, Andreas; Vo, Duc Duy; Irwin, John J.; show more...; Kihlberg, Jan; Brea, Jose; Isabel Loza, Mar ...; Carlsson, Jens; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Pharmaceutical S ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medicinal Chemis ...

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