Dark chemical matter as a promising starting point for drug lead discovery

Abstract

High-throughput screening (HTS) is an integral part of early drug discovery. Herein, we focused on those small molecules in a screening collection that have never shown biological activity despite having been exhaustively tested in HTS assays. These compounds are referred to as 'dark chemical matter' (DCM). We quantified DCM, validated it in quality control experiments, described its physicochemical properties and mapped it into chemical space. Through analysis of prospective reporter-gene assay, gene expression and yeast chemogenomics experiments, we evaluated the potential of DCM to show biological activity in future screens. We demonstrated that, despite the apparent lack of activity, occasionally these compounds can result in potent hits with unique activity and clean safety profiles, which makes them valuable starting points for lead optimization efforts. Among the identified DCM hits was a new antifungal chemotype with strong activity against the pathogen Cryptococcus neoformans but little activity at targets relevant to human safety.

Divergent Synthesis and Real-Time Biological Annotation of Optically Active Tetrahydrocyclopenta[c]pyranone Derivatives

“…1−4 Inclusion of diverse molecular shapes has been suggested as a key factor for library performance. 5−9 However, in contrast to natural products, many synthetic libraries contain only a few sp 3 -rich scaffolds.…”

Small-Molecule Screens: A Gateway to Cancer Therapeutic Agents with Case Studies of Food and Drug Administration–Approved Drugs

“…Assays that are more biologically and physiologically relevant will continue to result from recent advancements in three-dimensional tissue culturing, genomic editing, stem cell biology, and access to primary patient cells. Additionally, accumulating knowledge (within both public databases and the literature) about compound activity (Wassermann et al, 2015), reactivity (Dahlin et al, 2004), and interference (Simeonov et al, 2008;Baell and Walters, 2014) informs the selection of hit compounds from primary screens and influences the assembly and composition of small-molecule libraries. As always, the utility of all these advancements toward therapeutic development depends critically upon the continued efforts of basic researchers to unravel the complicated molecular details that drive human diseases.…”

Systematic chemical-genetic and chemical-chemical interaction datasets for prediction of compound synergism

“…By definition, the biological activity of such compounds would not be detected in many high-throughput screens used in modern drug discovery. Compounds with such latent activities have been termed cryptagens or dark chemical matter 10,11 .…”