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New chemotypes from virtual libraries: screening of Enamine REAL Database reveals in vivo hits

Melatonin (MT) receptors are established drug targets for aligning circadian phase in disorders of sleep and depression. But there are only a few in vivo hits reported to date. Enamine scientists along with the scientists from UCSF, UNC, USC, and other institutions participated in the research study aimed to fill the gap in therapeutics of these receptors.

150 million make-on-demand compounds from Enamine REAL Database were selected for initial hit finding via ultra-large docking against MT1 receptor. The REAL compounds with a structural fit and chemical novelty were prioritized. These high-ranking hits were delivered by Enamine via parallel synthesis for in vitro screens. Structure-based optimization led to two selective MT1 inverse agonists, topologically unrelated to previously explored chemotypes, that were tested in mouse models of circadian behavior. Unexpectedly, the MT1-selective inverse agonists advanced the phase of the mouse circadian clock, an agonist-like effect eliminated in MT1- but not in MT2-knockout mice.

We are proud to have these findings published in Nature. The results of this and the previous studies illustrate the opportunities for obtaining new, in vivo-active chemotypes from structure-based screens of diverse libraries of make-on-demand compounds.

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