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Drug Discov Today. 2018 Mar;23(3):481-486. doi: 10.1016/j.drudis.2017.07.003. Epub 2017 Jul 11.

Drugs as habitable planets in the space of dark chemical matter.

Author information

1
Structural Bioinformatics Group, Institute of Physiology & Experimental and Clinical Research Center (ECRC), Charité - University Medicine Berlin, Berlin, Germany; BB3R - Berlin Brandenburg 3R Graduate School, Free University of Berlin, Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
2
Structural Bioinformatics Group, Institute of Physiology & Experimental and Clinical Research Center (ECRC), Charité - University Medicine Berlin, Berlin, Germany; BB3R - Berlin Brandenburg 3R Graduate School, Free University of Berlin, Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. Electronic address: robert.preissner@charite.de.

Abstract

A recent study demonstrated antifungal activity of dark chemical matter (DCM) compounds that were otherwise inactive in more than 100 HTS assays. These compounds were proposed to possess unique activity and 'clean' safety profiles. Here, we present an outlook of the promiscuity and safety of these compounds by retrospectively comparing their chemical and biological spaces with those of drugs. Significant amounts of marketed drugs (16%), withdrawn drugs (16.5%) and natural compounds (3.5%) share structural identity with DCM. Compound promiscuity assessment indicates that dark matter compounds could potentially interact with multiple biological targets. Further, thousands of DCM compounds showed presence of frequent-hitting pan-assay interference compound (PAINS) substructures. In light of these observations, filtering these compounds from screening libraries can be an irrevocable loss.

PMID:
28709991
DOI:
10.1016/j.drudis.2017.07.003
[Indexed for MEDLINE]

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