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

AI Article Synopsis

  • High-throughput screening (HTS) is a crucial method in the early stages of drug discovery, focusing on identifying potential drug candidates from large collections of small molecules.
  • The study addresses 'dark chemical matter' (DCM), which includes compounds that have been extensively tested but showed no biological activity, aiming to identify their hidden potential.
  • The researchers found that some DCM compounds could lead to strong, unique biological activities, including a promising new antifungal agent with high effectiveness against Cryptococcus neoformans and a strong safety profile for human use.

Article 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.

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Source
http://dx.doi.org/10.1038/nchembio.1936DOI Listing

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