Drugs as habitable planets in the space of dark chemical matter

• Published in: Drug discovery today Vol. 23; no. 3; pp. 481 - 486
• Main Authors: Siramshetty, Vishal B., Preissner, Robert
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2018
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2017.07.003

[Display omitted] •Many marketed drugs and natural products are present in dark chemical matter.•Most drugs found in the dark chemical space are active against multiple targets.•Dark matter compounds remain unattractive despite the presence of PAINS.•Fate of compounds in screening libraries should not be decided based on 100 assays. 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 Significant amounts of marketed drugs (16%), withdrawn drugs (16.5%) and natural compounds (3.5%) share structural identity with DCM.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.