One of the main challenges in pharmaceutical chemistry is the discovery of specific ligands with no off-target activity. An alternative approach to search for selective modulators is to screen the dark chemical matter, a set of compounds that displayed no bioactivity despite being assayed at hundreds of different targets. We screened these compounds using structure-based docking against the A2A adenosine and the D4 dopamine receptors. A set of 53 top-ranked compounds was prioritized for experimental evaluation. Four ligands were discovered and the best compounds had submicromolar activity (Figure 1). We evaluated and confirmed the clean safety profiles and the low promiscuity of the hits through analysis of the PubChem Bioassay database. The physicochemical properties of the dark chemical matter were also analyzed and compared with those characterizing commercial screening libraries and bioactive compounds from ChEMBL, showing that dark and bioactive compounds are enriched in different regions of chemical space. Our results confirm that virtual screening provides an efficient means to mine the dark chemical space for leads of G protein-coupled receptors. A database containing the commercially available fraction of the dark chemical matter was composed and is freely available.

Docking finds GPCR ligands in dark chemical matter

ACS Fall 2020 Virtual Meeting

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