How To Hunt For Drugs In Dark Chemical Matter

The term DCM was coined by Wassermann and colleagues at Novartis and then refined with the input from researchers at Merck, after Wassermann switched camps (Refs. 1,2).  Jaisal and Bajorath recently revisited the topic as well (Ref. 3). In each publication, the approach has been to effect some sort of molecular fingerprint matching for searching through chemical libraries. The objective of the exercise is to identify sets of otherwise consistently inactive, e.g. negative in 50-100 assays, DCM compounds (DCMs) whose structural features coincide with closely related active compounds in biological or phenotypic domains for which the DCMs were never screened. In other words, DCM "Inactives" stand a chance to be "Brightened" or repurposed into "Actives".

Quoting Wassermann (Ref. 1), DCMs therefore "have the potential to be potent hits with little or no tar­get promiscuity and thus could present an opportunity for identify­ing new leads." Indeed, a solid and unexpected new antifungal chemotype emerged from this work "with strong activity against the pathogen Cryptococcus neoformans but little activity at targets relevant to human safety."  A less bullish but still optimistic view concluded her later work (Ref. 2): "dark compounds that become active in a screen of an on-going drug discovery project or through targeted profiling efforts may be considered as tool compounds for the respective biological process or protein target."

In the latest salvo on prospecting through DCM, the Bajorath group just set their cards on the table for all to see and avoided value judgment: "Analog series containing DCM and known bioactive compounds were generated on a large scale, making it possible to derive target hypotheses for more than 8000 extensively assayed DCM molecules" (Ref. 3 and accompanying open access deposition).