Identification of novel cannabinoid receptor ligands via evolutionary de novo design and rapid parallel synthesis

A rapid entry to novel and patentable cannabinoid receptor (CB-1) ligands has been identified using computer-based de novo design in combination with parallel synthesis. Small targeted compound arrays were readily prepared from the designs yielding active hit rates of 6% and 10%, respectively. This represents a hit rate enrichment of up to two orders of magnitude compared with corporate compound collections and is the first report of the application of the TOPAS algorithm for the de novo design of GPCR ligands.