Ultra-large virtual molecular libraries throw open chemical space

"A paper published this week demonstrates the power of ultra-large virtual libraries in helping researchers to look into the unknown (J. Lyu et al. Nature https://doi.org/10.1038/s41586-019-0917-9; 2019). In it, the authors built a virtual library of around 350 million drug-like molecules. They used this to simulate the ways that these molecules could interact with two therapeutically relevant proteins — AmpC β-lactamase, a target for antibiotics, and the D4dopamine receptor, linked to several neurological disorders and a member of the pharmacologically important family of G protein-coupled receptors....

After this virtual screening, the team synthesized the top-scoring compounds and tested them against the two targets. One of the compounds turned out to be the most potent inhibitor of AmpC β-lactamase known, and is chemically distinct from all other known inhibitors.

Of the 500 or so molecules the group made that targeted the D4 dopamine receptor, one had an unprecedented ability to stimulate it. This compound’s selectivity over other dopamine receptor types, and its preferential activation of the G protein signalling pathway, are both important properties that might help to minimize unwanted side effects when, and if, it’s used as a drug...."