Docking Finds GPCR Ligands in Dark Chemical Matter.

Ballante F, Rudling A, Zeifman A, Luttens A, Vo DD, Irwin JJ, Kihlberg J, Brea J, Loza MI, Carlsson J

J Med Chem 63 (2) 613-620 [2020-01-23; online 2020-01-13]

High-throughput screening has revealed dark chemical matter, a set of drug-like compounds that has never shown bioactivity despite being extensively assayed. If dark molecules are found active at a therapeutic target, their extraordinary selectivity profiles make excellent starting points for drug development. We explored if ligands of therapeutically relevant G-protein-coupled receptors could be discovered by structure-based virtual screening of the dark chemical matter. Molecular docking screens against crystal structures of the A2A adenosine and the D4 dopamine receptors were carried out, and 53 top-ranked molecules were evaluated experimentally. Two ligands of each receptor were discovered, and the most potent had sub-micromolar affinities. Analysis of bioactivity data showed that the ligands lacked activity at hundreds of off-targets, including several that are associated with adverse effects. Our results demonstrate that virtual screening provides an efficient means to mine the dark chemical space, which could contribute to development of drugs with improved safety profiles.

Jens Carlsson

SciLifeLab Fellow

PubMed 31846328

DOI 10.1021/acs.jmedchem.9b01560

Crossref 10.1021/acs.jmedchem.9b01560

Publications 9.5.0