Dark Chemical Matter (DCM) in screening deck

I was interested in the article, because of the title.
“The performance of dark chemical matter in high throughput screening”

What is dark chemical matter(DCM) ?
The definition of DCM is that compounds, which have been tested and found inactive in 50 or more assays, exhibit hit rates that are comparable to those of compounds tested in much fewer assays.
Are DCM compounds inert to any targets ? The author give me useful suggestion.
They used large amount of compounds and assay datasets.
Fig8 was interesting for me. Fig 8 shows a comparison of phys-chem properties of active compounds and DCM compounds. And active compounds shows a higher molecular weight, lower polarity ( high AlogP) and lower molecular solubility compared ti DCM compounds. And also active compounds showed a large number of aromatic rings!
Medicinal chemists design compounds library like escape from flat land, reduce lipophilicity and molecular weight etc… Does the approach reduce hit rate ?

But, they mentioned active compounds that have higher hit rate is most likely includes assay cross activity ( du to target similarity a.k.a. kinase ), general promiscuity of compounds, or assay artifacts.
Removing those bias, they found that the hit rates of compounds less tested do not differ much from the hit rates of DCM.
And they asserted that DCM offers a chance for potentially valuable hits. Because of they are more drug like compounds.

More details are described in the article. The article was very suggestive for me. I understood DCM is diamond in the rough. But I think that relation of compound and target is once-in-a-lifetime experience. How estimate a probability of hit rate….;-)




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