New insights from old data - Hunting for compounds with novel mechanisms using cellular high-throughput screening profiles with Grey Chemical Matter

25 August 2023, Version 1

Abstract

Identifying high quality chemical starting points is a critical and challenging step in drug discovery, which typically involves screening large compound libraries or repurposing of compounds with known mechanisms of actions (MoAs). Here we introduce a novel cheminformatics approach that mines existing large-scale, phenotypic high throughput screening (HTS) data. Our method aims to identify bioactive compounds with distinct and specific MoAs, serving as a valuable complement to existing focused library collections. This approach identifies chemotypes with selectivity across multiple cell-based assays and characterized by persistent and broad structure activity relationships (SAR). We prospectively demonstrate the validity of the approach in broad cellular profiling assays (cell painting, DRUG-seq, Promotor Signature Profiling) and chemical proteomics experiments where the compounds behave similarly to known chemogenetic libraries, but with a bias towards novel protein targets and required no synthetic effort to improve compound properties. A public set of such compounds is provided based on the PubChem BioAssay dataset for use by the scientific community.

Supplementary weblinks

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.